1. Introduction
The discovery of compounds with antibacterial activities has paved the way to rescue the lives of patients with serious infectious diseases. However, the rapid development of antibiotic-resistant bacterial strains has often led to treatment failure. Another medical challenge is biofilm-associated bacterial infections that are often difficult to treat due to the reduced antibiotic sensitivity of the sessile biofilm-embedded bacteria together with diminished penetrability of antibiotics through the extracellular matrix composed of extracellular polymeric substances (EPS) and other materials produced by the bacteria [1,2]. Biofilm-forming microorganisms are estimated to cause 65–80% of human infections [3,4]. Biofilms are communities of bacteria that are embedded in a hydrated, predominantly anionic matrix of bacterial exopolymers such as polysaccharides that have trapped other components from the bacteria or the surroundings including proteins, nucleic acids, lipids, teichoic acids, and various other organic molecules [1,2]. The production of EPS functions as an anchorage site for the adherence of additional bacteria. The microbes communicate with each other through quorum sensing (QS), which regulates the metabolic activity of the cells, promotes biofilm formation, and increases virulence [4]. Based on the central role of QS in the regulation of bacterial biofilm and virulence, several strategies have been developed to target this signaling system [4,5,6,7,8,9,10,11,12].
The biofilms can be formed on both biotic surfaces such as connective tissue, mucus, epithelium, endothelium, intestine, cardiac valves, bone marrow, and the skin [3,4,13,14], and abiotic surfaces such as prostheses, implants, stents, and catheters [4,14,15]. Biofilm-associated diseases include otitis media, chronic rhinosinusitis, pharyngitis, laryngitis, pneumonia, bacterial vaginosis, infective endocarditis, mastitis, atherosclerosis, osteomyelitis, meningitis, urinary tract infections, kidney infections, skin infections, and inflammatory bowel diseases [13,14,15]. Biofilms formed on biological tissues are a major etiological cause of chronic and recurrent infections. In addition, biofilm formation by oral cariogenic bacteria is associated with tooth decay and gingivitis [16]. The sessile biofilm-associated bacteria have been shown to be up to 100–1000 times more tolerant to antibiotics in comparison to the same bacteria in the planktonic state [15,17,18,19,20,21]. Thus, targeting biofilms would be a prominent approach to overcoming the antibiotic resistance of biofilm-associated infections.
Common bacteria involved in severe biofilm-associated infections include the pathogens of the “ESKAPE” group (Enterococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.), which cause a variety of infections such as skin and soft tissue infections of wounds, bacteremia, urinary tract infections, meningitis, and pneumonia [22,23,24,25,26,27,28,29]. The “ESKAPE” acronym is derived from the ability of these pathogens to “escape” from antimicrobial therapy and the defense mechanisms of the immune system. These bacteria are common causes of life-threatening nosocomial infections, especially in cystic fibrosis patients, critically ill, and immunocompromised individuals [25,27]. The bacteria can adhere to both biotic and abiotic surfaces and form biofilms that are difficult to eradicate. In addition, the bacteria frequently develop resistance to existing antibiotics, which urges the development of new therapeutic strategies.
This review deals with various aspects of the interrelationship between antibiotic resistance, QS, and biofilms with a specific emphasis on pathogenic bacteria of the “ESKAPE” group. The first part describes various mechanisms involved in antibiotic resistance. The second part describes quorum sensing and various two-component systems (TCSs) affecting antibiotic resistance. The third part discusses various factors including TCSs that affect biofilm formation and the impact of biofilms on antibiotic resistance. In the last section of the review, some strategies that have been developed to break the vicious communication between quorum sensing, biofilm, and antibiotic resistance are described. Due to the enormous number of publications describing these issues, we have restricted our review to selected examples, and apologize for omitting others. The general concept is emphasized.
2. Antibiotic Resistance Mechanisms
Although the introduction of antibiotics into the clinics is indispensable for the medical treatment of severe infections, their frequent uses have led to the spread of antibiotic-resistant bacterial strains that lead to treatment failure. There are multiple mechanisms that are involved in the acquisition of antibiotic resistance. Among them, drug resistance can be caused by: (i) the acquisition of various antibiotic-resistant genes via horizontal gene transfer; (ii) decreased membrane permeability; (iii) increased production of degrading enzymes that cleave and thus inactivate the antibiotics; (iv) increased production of antibiotic modification enzymes that inactivate the antibiotics; (v) alterations of the target that disable the binding of the antibiotics; (vi) overexpression of efflux pumps that lead to rapid extrusion of the drugs with consequent low intracellular drug concentration; (vii) expression of regulatory small RNAs (sRNAs); (viii) methyltransferases that methylate 16S and 23S rRNA, thus altering the antibiotic binding site with reduced drug affinity; (ix) mutations in rRNAs; (x) ribosomal protection; (xi) changes in the metabolic state of the bacteria; (xii) biofilm formation; (xiii) elevated nutrient sequestering mechanisms; (xiv) induction of antibiotic tolerance; (xv) appearance of persister cells [20,25,28,30,31,32,33,34,35,36,37,38] (Table 1).
Some organisms show intrinsic resistance to given antibiotics, while in others the resistance mechanism can be acquired, and even induced by the antibiotic itself resulting in adaptive resistance [39,40]. The adaptive resistance is usually transient and reversed after the removal of the triggering environmental factors. Adaptive resistance is a major mechanism of how persister cells evade antibiotics [41]. Due to the high mechanistic versatility of antibiotic resistance, it is not possible to include all of them in this review, and the readers are referred to comprehensive reviews elsewhere [28,30,31,35,39,42]. We will below describe in brief the major antibiotic resistance mechanisms with selected examples. The involvement of biofilm in antibiotic resistance will be discussed in Section 4.2.
Table 1Various antibiotic resistance mechanisms in Gram-positive and Gram-negative bacteria.
| Resistance Mechanism | Examples | References |
|---|---|---|
|
Reduced
|
|
[32,34,43,44,45] |
|
Antibiotic
|
|
[25,28,34,46,47] |
|
Antibiotic
|
|
[25,28,48,49,50] |
| Proteases and Peptidases |
|
[51,52,53,54] |
| Efflux pumps |
|
[55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77] |
|
Reduced
|
|
[78,79,80,81,82,83,84,85] |
|
Modification
|
|
[79,86,87,88,89,90,91,92,93] |
|
Target
|
|
[94,95,96,97] |
|
Ribosomal
|
|
[98,99,100,101,102,103] |
|
Biofilm-
|
|
[1,13,14,20,104,105,106] |
2.1. Acquisition of Various Antibiotic-Resistant Genes via Horizontal Gene Transfer
Bacteria show high genetic plasticity that enables the individual bacteria to develop different phenotypes in an ever-changing environment and to promote adaptive evolution, thus providing the bacteria with fitness traits and survival advantages [39]. The acquisition of antibiotic resistance-conferring genes can occur through horizontal gene transfer, including plasmids, gene cassettes in integrons, and transposons that can capture and disseminate genetic material across bacterial genomes.
The readiness for horizontal gene transfer of mobile genetic elements has led to the terminology “mobilome” [107]. Transposons are transposable elements capable of moving from one position to another within a given genome and are often associated with the dissemination of antimicrobial resistance determinants [42]. Integrons use site-specific recombination to move resistant genes between defined sites [42]. The mobile genetic elements are often present in multiple copies in different locations in the genome and can be transferred to other bacteria through intercellular mechanisms of genetic exchange such as conjugation, mobilization, bacteriophage-mediated transduction, and uptake of extracellular DNA by transformation [42]. For instance, Acinetobacter baumannii shows high genetic plasticity with a prominent ability to acquire plasmids [108], transposons [109], and integrons [110], conferring resistance against most classes of antibiotics.
A classic example of horizontal gene transfer resulting in antibiotic resistance is the plasmid-mediated colistin resistance by mobile colistin resistance (mcr) in Enterobacteriaceae that limits the clinical application of colistin as a last-line drug against bacterial infection [111,112]. Since its detection, several mcr genes have been characterized and they have been found in other bacterial species too [86]. Colistin (polymyxin E) acts by binding to negatively charged lipopolysaccharides (LPS) and phospholipids in the outer membrane of Gram-negative bacteria, resulting in increased permeability of the bacterial membrane, and consequent bacterial death [86]. The mcr genes encode for a phosphoethanolamine transferase that adds phosphoethanolamine to lipid A of LPS, thereby reducing the affinity of polymyxins to LPS [86].
Another example of horizontal gene transfer is the mobile genetic element staphylococcal chromosomal cassette (SCCmec) that carries the mecA and mecC genes encoding for the penicillin-binding protein (PBP) variant PBP2a with low affinity for β-lactams, and the site-specific recombinase genes ccrAB and ccrC that mediate the integration and excision of SCCmec into and from the chromosome [78]. After accurate excision and integration mediated by the site-specific recombinase genes ccrAB and ccrC, SCCmec is integrated into the staphylococcal chromosome, thus leading to the acquisition of β-lactam antibiotic resistance [78]. SCCmec is rapidly transferred between staphylococcal species and might be integrated several times within the same bacterial genome [113]. Various SCCmec elements are the underlying cause of the appearance of methicillin-resistant Staphylococcus aureus (MRSA) which poses a challenge to hospital infections [78].
2.2. Decreased Membrane Permeability
Since most antibiotics target intracellular processes, they need to penetrate the bacterial membrane. One mechanism of drug resistance can be achieved by preventing drug uptake. In Gram-negative bacteria, the outer membrane serves as a physical and functional barrier where lipid A modifications limit the interaction with drugs with a concomitant reduction in drug permeability [114]. The uptake of antibiotics in the Gram-negative bacteria requires, among others, the outer membrane porins (OMPs) which are transmembrane pore-forming proteins with a β-barrel structure that allows the passive transport of hydrophilic compounds including nutrients [32]. OPMs are also important for maintaining membrane integrity [32].
In Acinetobacter baumannii, the porin OmpAAb was found to be required for the uptake of β-lactams and sulbactam [115]. Reduced expression of some outer membrane proteins in Acinetobacter baumannii was associated with imipenem resistance [43,44]. Later studies showed that oprD and carO were downregulated in imipenem-resistant Acinetobacter baumannii in comparison to drug-sensitive species, together with an upregulation of an efflux pump [45]. Paradoxically, a ΔompA mutant of Acinetobacter baumannii was more sensitive to several antibiotics including aztreonam, nalidixic acid, chloramphenicol, and trimethoprim than the parental wild-type strain [116,117]. The increased susceptibility of the ΔompA mutant to antibiotics despite its involvement in antibiotic uptake might be explained by the increased outer membrane permeability to hydrophobic molecules when ompA is lacking [118], and the presence of other porins that contribute to the uptake of the antibiotics. Recently, the trimeric, porin-like DcaP was found to facilitate the permeation of the β-lactamase inhibitor sulbactam into these bacteria [119]. DcaP shows an abundance of positively charged residues which leads to a preferential transport of negatively charged substrates [119]. Besides the negatively charged β-lactamase inhibitors, this porin transports succinate and phthalates [119]. OmpA is also important for biofilm formation on both abiotic and biotic surfaces [120,121]. Compound 62520 inhibits ompA expression and prevents biofilm formation in Acinetobacter baumannii [122].
In Escherichia coli, the outer membrane expresses the two porins OmpF and OmpC [123]. An ompF-defective Escherichia coli mutant was resistant to several antibiotics including β-lactams, suggesting that OmpF functions as the main route of outer membrane penetration for many antibiotics [32,124]. Similar antibiotic resistance was observed in porin mutants of Klebsiella pneumoniae (ΔompK35) [125], Serratia marcescens (ΔompF) [126], Pseudomonas aeruginosa (ΔoprD) [127], and Enterobacter aerogenes (omp36 Gly112Asp mutant) [128]. In Klebsiella pneumoniae, which has developed resistance to ertapenem, the non-selective porins OmpK36 and OmpK35 were found to be reduced, lost, mutated, or truncated [34,129,130,131]. OmpK35 of Klebsiella pneumoniae forms large permeable porins with high permeability toward lipophilic (e.g., benzylpenicillin) and large (e.g., cefepime) antibiotics [125]. OmpF of Serratia marcescens is important for the penetration of nitrofurantoin and the β-lactams ampicillin and cefoxitin [126]. The omp36 mutant of Enterobacter aerogenes that has a substitution of Gly112Asp in the conserved eyelet L3 region of the porin, confers resistance to β-lactams [128]. Reduced expression of the porin protein OprD in Pseudomonas aeruginosa led to reduced drug influx of panipenem [132]. This channel is used by the bacteria to take up basic amino acids. The addition of basic amino acids such as L-lysine reduced the response to panipenem, suggesting a competition for the OprD channel [132].
The major OprF porin of Pseudomonas aeruginosa, a homolog to the OmpA of Enterobacteriaceae, appears mainly in the closed state, which might explain the low outer membrane permeability of these bacteria in comparison to other bacteria [133]. OprF anchors the outer membrane to the peptidoglycan layer and allows the diffusion of small polar nutrients including polysaccharides [134]. Of note, the absence of OprF in Pseudomonas aeruginosa caused an increase in biofilm formation and production of the Pel exopolysaccharide through upregulation of the second messenger bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP) [135]. These authors proposed that the absence of OprF leads to cell envelope stress that activates the SigX regulon that is involved in regulating c-di-GMP levels, which in turn regulates the pel and psl gene clusters. The PA1181 and adcA (PA4843) genes of the SigX regulon are involved in the increased c-di-GMP levels [135].
2.3. Increased Production of Antibiotic Degrading Enzymes
The classical examples of bacteria-produced enzymes that inactivate antibiotics are β-lactamases that cleave the β-lactam ring of penicillin [25,28] and carbapenemases that result in resistance to imipenem, ceftazidime, and ceftriaxone among others [25,28,34,136]. The β-lactam antibiotic methicillin was developed to resist β-lactam-mediated degradation, but rapidly after its introduction into the clinics, resistance to methicillin emerged in Staphylococcus aureus due to the SCCmec cassette carrying the mecA gene encoding for the low penicillin-binding protein PBP2a [78]. A different strategy to overcome resistance caused by β-lactamases is the use of β-lactamase inhibitors such as clavulanic acid, sulbactam, avibactam, and ETX2514 in combination with the β-lactam antibiotics [137].
Resistance to macrolide antibiotics such as erythromycin can emerge by the enzymatic cleavage of the macrolactone ring by erythromycin esterases encoded by the ereA-D genes [46,47]. The detoxification of macrolides adds to other mechanisms of macrolide resistance that include decreased intracellular concentration via the efflux pumps such as Mel and Mef [55], the expression of ermB gene product that methylates the peptidyl-transferase center of newly synthesized 23S rRNA conferring cross-resistance to lincosamides and streptogramin B (MLS phenotype) [79], mutations in 23S rRNA and ribosomal proteins L4 and L22 [79,80], ribosomal protection, e.g., by MsrE [98] and macrolide phosphotransferase mediated modification [49].
Enzymes of the Tet(X) family are flavin-dependent monooxygenases that inactivate tetracyclines including the last-resort antibiotic tigecycline by adding a hydroxyl group to the C-11a position, resulting in an unstable compound that undergoes auto-decomposition [50,138,139,140,141]. This has led to their nickname “tetracycline destructases” [142].
2.4. Increased Production of Antibiotic Modification Enzymes
The aminoglycoside-modifying enzymes (acetyltransferases, nucleotidyltranferases, and phosphotransferases) inactivate gentamicin and other aminoglycoside antibiotics by catalyzing hydroxyl/amino group modifications to the 2-deoxystreptamine nucleus of the sugar moieties [28,48]. Chloramphenicol acetyltransferase (CAT) detoxifies chloramphenicol by adding an acetyl group thereby preventing its binding to ribosomes [25,28].
2.5. Alterations of the Target That Disable the Binding of Antibiotics
Methicillin-resistant Staphylococcus aureus (MRSA) has acquired a PBP2 variant, PBP2a expressed on the SCCmec cassette [78]. This PBP2 variant shows low affinity to penicillin, thus enabling cell wall synthesis even in the presence of high concentrations of β-lactam drugs including methicillin [78]. Several variants of the SCCmec cassette have been observed [143].
Vancomycin, a glycopeptide antibiotic, acts by binding to the terminal D-alanyl–D-alanine dipeptide of peptidoglycan precursors, thereby interfering with bacterial wall synthesis. Acquired resistance to vancomycin is caused by the substitution of D-alanyl-D-lactate for the D-alanyl–D-alanine dipeptide, resulting in a 1000-fold lower affinity for vancomycin [87]. This modification is mediated by genes of the vanHAX operon. The vanHAX operon is regulated at the transcriptional level by the two-component VanR/VanS regulatory system in response to vancomycin [88]. In this case, vancomycin activates the membrane sensory kinase VanS, which, in turn, phosphorylates the transcription regulator VanR that drives the expression of the vanHAX operon [88,144] (Figure 1A). The van gene cluster has been found in human pathogens such as Enterococcus faecalis, Enterococcus faecium, and Staphylococcus aureus [88].
The zinc-dependent D, D-carboxypeptidases VanX, and VanY act by hydrolyzing the dipeptide (D-Ala-D-Ala) and pentapeptide (UDP-MurNac-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala), respectively, and confer vancomycin resistance in Enterococci by eliminating the substrate D-Ala-D-Ala [54,145,146].
2.6. Overexpression of Efflux Pumps
A frequent reason for drug resistance is the elevated expression of various efflux pumps that extrude the drugs, thereby reducing the intracellular concentration of the antibiotics below the required minimum inhibitory concentration (MIC) [28]. Efflux pumps, in general, regulate the intracellular environment by extruding toxic substrates including secondary metabolites, QS molecules, dyes, biocides, bile acids, hormones, host defense molecules, fatty acids, detergents, heavy metals, organic pollutants, and antibiotics [31,77,147,148,149,150]. In addition, some efflux pumps have a role in the colonization and the persistence of bacteria in the host [151]. Efflux pumps may affect virulence and biofilm formation by excreting extracellular matrix proteins and QS molecules that coordinate biofilm formation, and by affecting surface adhesion [151,152,153,154,155,156,157,158].
The efflux pumps can be categorized into different families based on the amino acid sequence identity, the energy source required to drive export, and the substrate specificities. The major efflux pump families include the resistance-nodulation-cell division family (RND), the major facilitator superfamily (MFS), the multidrug and toxic compound extrusion family (MATE), the small multidrug resistance family (SMR), ATP-binding cassette family (ABC), and the proteobacterial antimicrobial compound efflux family (PACE) [77,152,159,160]. The ABC superfamily belongs to the primary active transporters that use ATP hydrolysis as the energy source, while the other efflux family members are secondary active transporters (symporters, antiporters, and uniporters) that use energy from proton and/or sodium gradient [77,161,162]. The RDN superfamily is only found in Gram-negative bacteria, while the other efflux pump families are found in both Gram-negative and Gram-positive bacteria [163]. Efflux pumps are either single-component transporters catalyzing the drug efflux across the inner cytoplasmic membrane, or multiple-component systems composed of an inner membrane transporter, periplasmic adaptor, and an outer membrane channel [163,164]. The three components in the latter type of efflux pumps (usually belonging to the RDN family) function together to promote the efflux across both the inner and outer membrane of Gram-negative bacteria [163]. Examples of RDN efflux pumps are the AcrAB-TolC of Escherichia coli and Salmonella typhimurium, and MexAB-OprM and MexXY-OprM of Pseudomonas aeruginosa [163]. EmrE of Escherichia coli and QacC of Staphylococcus aureus belong to the SMR family, while NorA and QacA of Staphylococcus aureus and PmrA of Streptococcus pneumoniae belong to the MFS family [163,165]. PmpM of Pseudomonas aeruginosa and MepA of Staphylococcus aureus are examples of efflux pumps belonging to the MATE family, and AbcA of Staphylococcus aureus and LmrA of Lactococcus lactis belong to the ABC superfamily [163,165].
2.6.1. Inducible Efflux Pumps
The activities of many regulators of the efflux pumps are frequently affected by the substrates that will be transported by the regulated efflux pump [166,167,168,169,170]. These regulators usually contain a drug-binding pocket within the ligand-binding domain, and the binding of the drug to these regulators modulates their transcriptional repressor/activator activities [171,172,173,174]. The best-understood example of the regulation of a gene encoding the regulation of a drug exporter is the control of tetA expression by the specific repressor protein TetR [172,175]. Tetracycline binds to TetR, resulting in the transcription of the tetA efflux pump [172,175]. The Staphylococcus aureus multidrug transporter QacA is transcriptionally repressed by QacR, which interacts with similar substrates as QacA including chlorhexidine digluconate, benzalkonium chloride, and cetylpyridinium chloride [176]. Upon exposure to these compounds, QacR is released from the qacA promoter, resulting in the upregulation of QacA [176]. In Escherichia coli, EmrR is a negative regulator of the gene encoding the macrolide efflux pump emrAB, the repression of which is relieved upon binding of substrates such as tetrachlorosalicylanilide to EmrR [177,178]. Mutations in emrR in Salmonella typhi and Salmonella enterica cause an upregulation of emrAB with consequently reduced susceptibility to ciprofloxacin and other antibiotics [179,180]. Norfloxacin induces the expression of the norA efflux pump in Staphylococcus aureus [181]. NorA expression is regulated by the ArlRS QS system [182], NorR [183], NorG [184], and MgrA [185] (Figure 1B). Mupirocin induces the expression of the efflux pumps NorA and MepA, resulting in resistance induction to norfloxacin and chlorhexidine [186].
The macrolide erythromycin induced the expression of the mefE-mel efflux pumps in Streptococcus pneumoniae by specific interactions of the macrolide C-5 saccharide with the ribosome that alleviate transcriptional attenuation of mefE-mel [61]. Transcriptional attenuation occurs when the secondary structure of the leader sequence of the transcript terminates transcription in a rho-independent manner [61]. Additionally, certain antimicrobial peptides such as LL-37 activate the transcription of mefE-mel, resulting in the resistance to erythromycin [187].
The MexXY-OprM efflux pump in Pseudomonas aeruginosa can be induced by ribosome-targeting antibiotics such as chloramphenicol, tetracycline, macrolides, and aminoglycosides [188,189,190] (Figure 2). Mutations in the fmt gene that encodes for methionyl-tRNA formyltransferase, or the folD gene, a component of the folate biosynthesis pathway, led to impaired protein synthesis and upregulation of mexXY [191]. Additionally, mutations in the ribosomal proteins L1 (encoded by rplA) and L25 (encoded by rplY) resulted in an upregulation of mexXY, further supporting a functional link between mexXY transcription and ribosome dysfunction [192,193]. Stalling of ribosomes at the PA5471 leader peptide (PA5471.1) leads to the transcription of PA5471 that upregulates the expression of mexXY through releasing the repressive action of MexZ [194,195]. mexXY expression is also regulated by MexR [196] and the QS systems ParRS [66] and AmgRS [197]. MexZ is frequently mutated in aminoglycoside-resistant Pseudomonas aeruginosa clinical isolates [198,199,200]. Calcium and magnesium ions could antagonize aminoglycoside efflux through MexXY-OprM [65].
Pathogens that survive in the intestine have often developed resistance mechanisms to the hazardous effects of bile acids [201] (Figure 3). One mechanism is the expression of the AcrAB efflux pump in the Enterobacteriaceae family including Escherichia coli, Salmonella, Shigella, and Klebsiella [202]. Other resistance mechanisms include the production of bile salt hydrolase that deconjugates bile acids and neutralizes its antimicrobial activity [203] and the expression of the signaling protein IreK (PrkC) that maintains cell wall integrity resulting in resistance to bile salts and cell wall active antibiotics such as cephalosporins [204,205]. Bile salts induce the expression of the efflux pumps emrB and qacA in Enterococcus faecalis, resulting in the simultaneous acquisition of resistance to various antibiotics [206]. In Pseudomonas aeruginosa, bile salts induced the expression of mexAB-oprM and some other efflux pumps, resulting in resistance to macrolide antibiotics and polymyxin [207]. Bile salts also activate various QS two-component systems (QS TCSs) resulting in increased bacterial virulence. In Lactobacillus rhamnosus GG, bile salts increased the expression of baeRS, phoRP3, and vraRS [208]. In Escherichia coli, bile salts led to the upregulation of the acrAB efflux pump, the TCSs basRS, and pmrAB, as well as lipid A modification genes (arnBCADTEF and ugd), resulting in cross-resistance to polymyxin [209]. The TCSs BcrXRS and LiaFSR were found to contribute to bile salt resistance in Enterococcus faecium [210]. The TCS CpxAR conferred bile acid resistance in Klebsiella pneumoniae [211].
The metabolite indole that is produced by the degradation of tryptophan by Escherichia coli and other gut bacteria was shown to induce the expression of the efflux pumps acdD and mdtABC in Escherichia coli through a mechanism involving the TCSs BaeSR and CpxAR [212] (Figure 4). In this study, the transcriptional induction by CpxAR required BaeSR, while BaeSR could act alone, suggesting that BaeR is the primary regulator, while CpxR enhances the effect of BaeR [212]. The induction of the efflux pump mdtE by indole in Escherichia coli was mediated by transcriptional regulator GadX [212]. Moreover, indole was shown to act as an intercellular signaling molecule that induces RamA-mediated upregulation of the acrAB multidrug efflux pump in Salmonella enterica, with the consequent acquisition of drug resistance [213,214]. Indole is excreted from Escherichia coli via the AcrEF-TolC efflux pump [215].
2.6.2. Mechanisms Resulting in Constitutive Overexpression of Efflux Pump
Besides being induced by antibiotics and various other toxic compounds for the bacteria, the expression of the efflux pump is regulated by QS (see Section 3), various stress stimuli (e.g., membrane disruption, protein misfolding), changes in metabolic state, and when the bacteria are embedded in a biofilm (see Section 4) [31,64,77,216]. Moreover, additional factors can result in the constitutive overexpression of efflux pumps, including (i) mutations in the local repressor gene; (ii) mutations in a global regulatory gene; (iii) mutations in the promoter region of the efflux gene; (iv) insertion elements upstream of the efflux pump gene [164,165]. Due to the multiple regulatory mechanisms, only selected examples will be highlighted here.
In Klebsiella pneumoniae, resistance to tigecycline can be caused by mutations in ramR, acrR, and rpsJ [217,218]. RamR represses the transcription of ramA [219], which regulates the multidrug efflux pump AcrAB-TolC [220]. Transformation of ramR mutant strains of Klebsiella pneumonia with the wild-type ramR gene restored susceptibility to tigecycline [219]. ramR mutations in a Salmonella enterica serovar Typhimurium strain led to overexpression of ramA and consequent overproduction of the AcrAB efflux pump [221]. A 2-nucleotide deletion in the putative RamR binding site of the ramA promoter was found to confer resistance to fluoroquinolones [221].
The AcrAB-TolC efflux pump is also regulated by the stress-response regulators MarA, RarA, SoxS, and RobA [149,222,223,224] (Figure 5). In tolC mutant bacteria, the two QS systems for sensing extracytoplasmic stress BaeRS and CpxARP were upregulated along with the upregulation of MarA, SoxS, and RobA [149]. RarA also regulates the expression of the oqxAB efflux genes and the porin ompF [222].
Insertion sequence (IS) elements that disrupt the function of regulatory proteins can upregulate the expression of acrAB, adeABC, and kpgABC efflux pump genes in Escherichia coli, Acinetobacter baumannii, and Klebsiella pneumoniae, respectively, resulting in tigecycline resistance [225,226,227]. IS1 elements were found to disrupt the function of AcrR, a repressor of acrAB in Escherichia coli [225]. Fluoroquinonolone resistance in a Salmonella enterica serovar Typhimurium strain was found to be due to an activation insertion sequence (IS1 or IS10) integrated upstream of the acrEF operon that encodes for the acrEF efflux pump [228].
2.6.3. Major Efflux Pumps in Pseudomonas aeruginosa
Pseudomonas aeruginosa contains a large number of efflux pumps, with four potent RND-type multidrug resistance efflux pumps (Mex) capable of eliminating toxic compounds from the periplasm and cytoplasm. These efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM) have overlapping spectra of antibiotic substrates and confer resistance to carbapenems, fluoroquinolones, and/or aminoglycosides [25]. The MexAB and MexCD are located in the inner membrane, while the OprM and OprJ are in the outer membrane [64]. The mexAB-oprM operon is repressed by MexR [196] and NalD [229], while activated by BrlR [230] and CpxR [231] (Figure 6). The mexCD-oprJ operon is repressed by NfxB [232]; and the mexEF-oprN operon is repressed by NfxC, while activated by the MexT transcriptional activator [233]. Mutation in MexR or NalC results in upregulation of mexAB-oprM, and resistance to aztreonam [234,235,236].
The efflux pump MexHI-OpmD exports the toxic metabolite anthranilate that serves as a precursor of the autoinducer PQS [237]. Pseudomonas aeruginosa lacking a functional MexHI-OpmD pump showed impaired growth due to accumulation of the toxic anthranilate [237]. The MexHI-OpmD efflux pump confers resistance to vanadium, norfloxacin, and acriflavine [237]. However, mutants lacking MexHI-OpmD became less sensitive to tetracycline, chloramphenicol, and rifampicin, and resistant to kanamycin and spectinomycin [237]. Extracellular addition of the autoinducer PQS increased the susceptibility of both the mexI and opmD mutant strains as well as the wild-type strain to these antibiotics [237]. MexHI-OpmD is upregulated by the endogenous 5-methylphenazine-1-carboxylate which is a substrate of this efflux pump and required for normal Pseudomonas aeruginosa biofilm morphogenesis [238]. 5-methylphenazine-1-carboxylate is an intermediate metabolite formed during the conversion of phenazine-1-carboxylic acid to the virulence factor pyocyanin (5-N-methyl-1-hydroxyphenazine) [238]. Pyocyanin upregulates mexHI-opmD through activation of the redox-responding transcription factor SoxR [239].
2.6.4. Major Efflux Pumps in Enterobacter spp.
The AcrAB-TolC tripartite multidrug efflux pump of Enterobacter species belongs to the RND superfamily and forms a tripartite complex consisting of an inner membrane pump protein (AcrB) and an outer membrane channel protein (TolC) bridged by a periplasmic adaptor protein (AcrA) [77]. It utilizes the proton motive force as an energy source to extrude the various substrates [56]. This efflux pump is essential for bacterial survival, particularly in the presence of toxic agents. Subinhibitory concentrations of ertapenem induced the expression of the regulator of antibiotic resistance A (rarA) that upregulates the expression of acrAB-tolC [40]. The expression of the acrAB and tolC genes are upregulated by the AraC-type transcriptional activators MarA, RamA, and SoxS [224,240,241]. acrAB is also upregulated by the QS regulator SdiA [242], while repressed by the transcriptional regulators AcrR [243] and Rob [244]. Bile salts and fatty acids bind to the C-terminal part of Rob, inducing a conformational alteration that results in the transcriptional activation of acrAB [244] (Figure 5).
The multidrug-resistant operon marRAB encodes the repressor marR, the activator marA, and the repressor marB which reduces the rate of marA transcription [245,246]. The operon is activated by compounds such as salicylate, chloramphenicol, tetracycline, acetaminophen, and sodium benzoate [247,248]. marA was found to be upregulated by the TCS QseBC in Escherichia coli through directly binding of QseB to the marA promoter [249]. MarA causes a decreased production of the ompF porin in Escherichia coli by activating the transcription of micF, an antisense RNA that binds to ompF mRNA, preventing its translation [250]. The OqxAB efflux pump was shown to be regulated by the AraC multidrug-resistant regulators RamA and RarA [222,241,251]. The transcription factor SoxR is oxidized in response to oxidative stress stimuli resulting in the activation of SoxS [252,253,254]. The SoxRS response protects the cells against superoxide toxicity [252], among others by inducing sodA [255]. SoxA also induced the expression of the acrAB-tolC efflux pump in Klebsiella pneumoniae with concomitant resistance to tetracycline [255].
2.6.5. Major Efflux Pumps in Staphylococcus aureus Contributing to the MRSA and MDRSA Phenotypes
More than 30 efflux genes have been characterized in Staphylococcus aureus [57]. Among these, NorA-C, MepA, and MdeA pump out fluoroquinolones and quaternary ammonium compounds (QACs), and the efflux pumps SepA and QacA/B extrude QACs and biguanidines such as chlorhexidine [57]. The norA gene is overexpressed in around 50% of Staphylococcus aureus strains and contributes to antibiotic-resistant strains [256,257].
The multidrug efflux pump AbcA that confers resistance to β-lactam antibiotics, moenomycin, and daptomycin in Staphylococcus aureus, is regulated by the transcription factors NorG, Rot, SarA, SarZ, MgrA, and the QS system AgrBDCA [258,259,260] (Figure 1B). In addition, AbcA is involved in the secretion of the phenol-soluble modulins (PSMs) [71,72], which are cytolytic toxins that lyse erythrocytes and neutrophils and play important roles in Staphylococcus aureus infections [51,261,262]. AbcA also affects cell wall autolysis [260]. Subinhibitory concentrations of ampicillin increased the expression of abcA and the surface proteins clfB, isdA, and sasG with a concomitant increase in biofilm formation [263].
2.7. Involvement of rRNA Methyltransferase in Antibiotic Resistance
Dimethylation of a specific nucleotide residue in the 23S ribosomal RNA by erythromycin resistance methyltransferase (erm) protects bacteria from macrolide antibiotics [89]. The majority of the erm genes are induced by the macrolide antibiotics, which is likely due to the reduced fitness caused by the ribosomal modification [89,264]. The Cfr methyltransferases methylate 23S ribosomal RNA, thereby preventing the binding of antibiotics to the peptidyl-transferase center [92]. Crf genes have been shown to confer resistance to chloramphenicol, clindamycin, linezolid, pleuromutilins, streptogramin A, and macrolide antibiotics [92,93].
2.8. Involvement of DNA Methyltransferase in Antibiotic Resistance
The DNA methyltransferase VchM was found to be required for the sensitivity of Vibrio cholerae to aminoglycosides [265]. VchM is an m5C DNA methylase that methylates cytosine at 5′-RCCGGY-3′ motifs. The lack of VchM results in increased expression of groESL-2 chaperone genes and tolerance to aminoglycosides, likely by capturing aminoglycoside-induced misfolded proteins [265].
2.9. Involvement of Ribosomal Protection in Antibiotic Resistance
Ribosomal protection proteins (RPPs) are involved in conferring antibiotic resistance toward ribosome-targeting antibiotics [103,266]. The ribosomal protection proteins TetM, TetO, TetS, TetT, TetQ, TetB, and TetW confer resistance to tetracycline antibiotics by releasing the drugs from the 30S ribosomal subunit or by preventing their binding to the ribosome [103]. These RPPs exhibit GTPase activity, bind ribosomes analogously to elongation factors, and displace ribosomal-bound antibiotics [103]. The GTP hydrolysis depends on the binding of the RPP to the ribosome and occurs only after correct codon-anticodon interaction [103]. After the release of the drug, GTP is hydrolyzed and the Tet RRP dissociates from the ribosome, enabling the ribosome to continue the elongation cycle [103].
The ATP-binding cassette (ABC) proteins of the F-subtype (ABC-F) confer resistance to several antibiotics such as lincosamides, pleuromutilins, streptogramin A, and oxazolidinones that target the ribosome peptidyl-transferase center (PTC) of the 50S large ribosomal subunit, and antibiotics such as macrolides and streptogramin B that target the adjacent nascent peptide exit tunnel (NPET) region of the 50S large ribosomal subunit [100,102,267]. The ABC-F proteins are ATPases that confer antibiotic resistance via ribosomal protection mechanism by interacting with the ribosome and displacing the bound drug, thus alleviating the translational inhibition caused by the antibiotics [99,100,268]. Examples are the LsaA and OptrA of Enterococcus faecalis, VgaA of Staphylococcus aureus, and VgaL of Listeria monocytogenes that confer resistance to PTC-binding antibiotics, and the macrolide and streptogramin B resistance (Msr) proteins such as MsrE of Pseudomonas aeruginosa, that confer resistance to NPET-binding antibiotics [101,102,268,269].
2.10. Involvement of Non-Coding RNAs in Antibiotic Resistance
Bacterial non-coding RNAs (ncRNAs), although not translated into functional proteins, can regulate sensitivity to antibiotics [33,270] as well as biofilm formation [271,272,273,274,275,276], virulence [277,278,279,280,281], and stress responses [280,282,283,284] by modulating gene expression. Some regulatory ncRNAs (rRNAs) reside in the 5’UTR of the regulated gene and sense the presence of the antibiotics by recruiting translating ribosomes onto short upstream open reading frames embedded in the ncRNA. In the presence of translation-inhibiting antibiotics, ribosomes arrest over the upstream open reading frames, altering the RNA structure of the regulator and thus activating the transcription of the resistance gene [33]. The ciprofloxacin stress-induced ncRNA CsiR was found to regulate in a negative manner ciprofloxacin resistance in Proteus vulgaris by targeting the efflux pump emrB [285]. CsiR-deficient strains were less sensitive to ciprofloxacin than the wild-type strain [285].
A ribosome-dependent riboregulation is involved in controlling the expression of the Staphylococcus aureus macrolide resistance methyltransferase ermC gene [286]. In the absence of erythromycin, ermC expression is repressed because the ribosome-binding site and AUG start codon of the ermC mRNA are sequestered in a stem-loop structure [286]. However, in the presence of erythromycin, ribosomes translating the ErmCL leader peptide become stalled, leading to an alternative stem-loop structure in the ermC mRNA that exposes the ribosome-binding site and start codon of the ermC gene and thus allows ribosome binding and induction of ermC expression [286].
Overexpression of the small RNA SprX in Staphylococcus aureus increased the sensitivity of the bacteria to the glycopeptide antibiotics teichoplanin and vancomycin [270]. An spxR deletion mutant showed reduced sensitivity to these antibiotics [270]. SprX inhibits the expression of the RNA-binding protein SpoVG [270], which is involved in bacterial resistance to methicillin, oxacillin, and glycopeptide antibiotics, among others, through promoting cell wall synthesis and inhibiting cell wall degradation [287,288]. SpoVG positively regulates the two-component system LysSR resulting in the activation of the antiholin lrgA and repression of the murein hydrolase lytN [270]. Overexpression of LrgA inhibits murein hydrolase activity and reduces the sensitivity of Staphylococcus aureus to penicillin [289] (Figure 7).
2.11. Involvement of Bacterial Proteases in Antibiotic Resistance
Bacterial-produced proteases (e.g., SepA) can degrade and thus inactivate antimicrobial peptides [51]. Various membrane proteases in Pseudomonas aeruginosa could confer resistance to aminoglycoside antibiotics [52]. Deletion mutation of the ftsH gene or insertion inactivation of two FtsH protease accessory factors (HflK and HflC) and the cytoplasmic protease HslUV increased the bacterial sensitivity to tobramycin [52]. Additionally, YccA, a modulator of FtsH, and the membrane protease HtpX conferred resistance to aminoglycosides [52]. The expression of the two latter gene products is regulated by the AmgRS two-component system [52]. The authors proposed that the proteases conferred resistance to aminoglycosides through the elimination of membrane-disruptive mistranslation products [52].
3. Quorum Sensing
Quorum sensing (QS) is an intercellular signaling mechanism that allows the communication between bacteria in a cell density-dependent manner [290]. The QS signaling system enables the bacteria to modify their gene expression pattern in response to changes in the environmental conditions, such as nutrient starvation, alterations in temperature, pH and osmolarity, oxidative stress, membrane stresses, antibiotics, and other toxic substances. It provides the bacteria with a selective survival advantage under different harsh conditions. Among others, the QS signaling cascade modulates cellular functions such as metabolic activity, extracellular polymeric substance (EPS) production, nutrient acquisition, transfer of genetic material between the cells, motility, biofilm formation, antibiotic resistance, virulence, and the synthesis of secondary metabolites [4,5,290,291,292,293,294,295,296]. In Pseudomonas aeruginosa, QS may also increase the resistance to oxidative stress stimuli by increasing the expression of catalase and superoxide dismutase [297].
The QS system usually involves the secretion of small molecules (autoinducers) that act on surface receptors on adjacent bacteria resulting in the induction of signal transduction pathways regulating biofilm formation, virulence, competence, conjugation, antibiotic resistance, motility, and sporulation [290,298,299,300]. These sensor–regulator pairs are called two-component systems (TCS) and involve phosphotransfer and phosphorelay that activates specific transcriptional regulators [290]. Usually, one of the TCS components encodes the autoinducer, while the other is the receptor that responds to the autoinducer. The sensor receptor is often membrane-bound and consists of an N-terminal sensor domain linked to a C-terminal cytoplasmic histidine kinase that autophosphorylates a conserved histidine residue in its own domain upon receptor activation. The sensor domains can, among others, detect changes in pH, temperature, and osmolarity. To ensure the transfer of the phosphoryl group from the sensor receptor kinase to the response regulator, an intermediate histidine phosphotransfer module (Hpt) is often required [290,301,302]. Phosphorylation of the response regulator leads to conformational changes resulting in altered affinity of the effector domain for its target DNA. As a result, the activation of TCS results in extensive alterations in gene expression. To emphasize the complexity of the bacterial QS system, more than 127 TCS members have been identified in Pseudomonas aeruginosa [303,304,305], versus 62 in Escherichia coli [306], 70 in Bacillus subtilis [307], 17 in Staphylococcus aureus [308,309,310,311], 15 in Enterococcus faecalis [312], and more than 20 in Acinetobacter baumannii [313].
Usually, the QS molecules in Gram-positive bacteria are oligopeptides such as autoinducing peptides (AIP), while in Gram-negative bacteria they belong to the family of N-acyl-L-homoserine lactones (AHL) [290,314,315,316,317,318]. The activation of the QS signaling system is usually induced when the autoinducer concentrations reach a threshold level, which occurs at higher cell densities. When activated, the QS leads to the large transcriptional alterations of hundreds of genes in the bacterial genome [290].
The transportation of autoinducers into the extracellular space is essential for their function as ligands for the respective receptors. Some autoinducers such as 3-oxohexanoyl homoserine lactone (3-Oxo-C6-HSL) from Vibrio fischeri and N-butyryl homoserine lactone (PAI-2) of Pseudomonas aeruginosa, are freely diffusible across the bacterial membranes [319,320]. However, other autoinducers, e.g., N-(3-oxododecanoyl) homoserine lactone (3-Oxo-C12-HSL, PAI-1) and 2-heptyl-3-hydroxy-4-quinolone (PQS) of Pseudomonas aeruginosa require a trafficking system [320,321]. One trafficking mechanism is the packaging of the autoinducers into membrane vesicles that are released from the bacteria [321]. The autoinducer PAI-1 of Pseudomonas aeruginosa is exported by the MexAB-OprM efflux system [320,322,323], while the autoinducers C4-homoserine lactone (C4-HSL) and 2-heptyl-3-hydroxy-4-quinolone (Pseudomonas quinolone signal, PQS), as well as the precursor 4-hydroxy-2-heptylquinoline (HHQ), are extruded by the MexEF-OprN efflux pump [324,325]. The overexpression of these efflux pumps in Pseudomonas aeruginosa reduces the intracellular autoinducer levels with concomitant diminished QS signaling [322,324]. Loss of MexAB-OprM caused increased QS responses [323].
3.1. TCSs in Vibrio Strains
The QS in various Vibrio strains including Vibrio fischeri, Vibrio harveyi, and Vibrio cholerae has been extensively studied [290,326,327,328]. The two major autoinducers in Vibrio cholerae are (S)-3-hydroxytridecan-4-one (cholera autoinducer-1; CAI-1) produced by CqsA and 4,5-dihydroxy-2,3-pentanedione (autoinducer-2; AI-2) synthesized by LuxS [327,329,330]. CAI-1 and AI-2 act on the membrane-bound receptors CqsR and LuxPQ, respectively, resulting in the dephosphorylation of LuxO, with concomitant reduced expression of the regulatory small RNAs qrr1-4, reduced expression of the AphA regulator, but increased expression of the HapR regulator [331,332,333]. AphA activates genes required for biofilm formation and pathogenicity [334], while HapR prevents biofilm formation by repressing the transcriptional activator vpsT [335]. HapR induces the expression of genes encoding proteases that promote Vibrio cholerae dispersion [336]. A third QS system of Vibrio cholerae is mediated by the autoinducer 3,5-dimethylpyrazin-2-ol (DPO), which activates the transcription factor VqmA, resulting in the expression of the small regulatory RNA vqmR [328]. VqmR, in turn, represses genes required for biofilm formation [328]. In Vibrio harveyi and Vibrio fischeri, the autoinducers activate a signal transduction pathway that leads to the activation of the master regulator LuxR that induces bioluminescence and biofilm formation [337,338,339,340].
Homologs of LuxS have been found in many different Gram-positive and Gram-negative bacterial species, suggesting interbacterial communication [341,342,343,344,345]. Moreover, bacteria can respond to autoinducers produced by other bacteria. For instance, Escherichia coli and Salmonella enterica serovar Typhimurium detect autoinducers produced by other bacteria through the orphan receptor SdiA which is a homolog to LuxR [346,347]. In addition, the dCACHE-domain proteins PctA/TlpQ in Pseudomonas aeruginosa function as a receptor for AI-2 [348]. The AI-2 (R-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran) produced by LuxS in Escherichia coli interacts with its receptor LsrB that regulates the cognate signal kinase LsrK and the activity of the transcriptional repressor LsrR [349,350].
Besides function as an AI-2 synthase, LuxS plays a central role in the metabolic activated methyl cycle (AMC), which is involved in the recycling of S-adenosylmethionine (SAM), a major methyl donor of the cell [341]. Thus, inactivation of luxS could result in changes in gene expression due to defective signaling, methionine metabolism, or accumulation of intermediates of S-adenosylmethionine metabolism [341].
3.2. TCSs in Pseudomonas aeruginosa
The rapid adaption of Pseudomonas aeruginosa to environmental stress conditions has been attributed to the high percentage of the genome encoding TCS elements (64 genes encoding response regulators and 63 histidine kinases) as well as 16 atypical kinases [305]. The major QS systems of Pseudomonas aeruginosa rely on the LasI/LasR, RhlI/RhlR, PqsABCDE/PqsR (MvfR), and the AmbBCDE/IqsR TCSs involved in the communal response to extracellular signaling autoinducer molecules, such as N-(3-oxododecanoyl) homoserine lactone (3-Oxo-C12-HSL) encoded by LasI, N-butyryl-L-homoserine lactone (C4-HSL) encoded by RhlI, 2-heptyl-3-hydroxy-4-quinolone (PQS) by PqsABCD and PqsH, and 2-(2-hydroxyphenyl)-thiazole-4-carbaldehyde (IQS) by AmbBCDE [296,351,352]. In the Las system, the transcription factor LasR is activated by the autoinducer 3OH-C12-HSL, and then LasR drives LasI expression and triggers the production of exotoxin A, the LasA protease, and the LasB elastase. In the Rhl TCS, the autoinducer C4-HSL increases RhlI expression by the binding and interaction of C4-HSL with RhlR and induces controlled production of the LasB elastase, rhamnolipids, pyocyanin, and cytotoxic lectins that play crucial roles in virulence and biofilm formation and development. The Las, Rhl, Pqs, and Iqs QS systems are hierarchically connected [296,353,354] (Figure 8). The Rhl and Pqs systems are regulated by the LasR/C12-HSL complex at the transcriptional and posttranscriptional levels [353,355,356]. The genes regulated by LasR and RhlR are involved in biofilm formation, bacterial motility, virulence, and antibiotic resistance. PqsE regulates a range of genes involved in biofilm formation, virulence, and antioxidative processes by serving as a link between the Las and Rhl QS systems [357,358,359,360,361]. Under conditions of low phosphate concentrations, the IQS QS system is activated and promotes biofilm formation through the Rhl and Pqs QS systems [362].
A regulatory network between β-lactam resistance, alginate production, QS, and virulence factors has been shown to exist in Pseudomonas aeruginosa [363]. In the presence of β-lactam antibiotics and the β-lactam antibiotic resistance master regulator AmpR, the sigma factor AlgT/U upregulates ampR gene expression, while AmpR represses algT/U gene expression, generating a negative regulatory feedback loop [363]. In the absence of ampR, there is an increase in the transcription of the QS components lasI and lasR, with a concomitant increase in alginate and pyocyanin production, increased LasA staphylolytic protease activity, and elevated expression levels of the two inducible β-lactamase genes, ampC and poxB [363,364]. AmpR also modulates antibiotic resistance to other antibiotics by regulating the expression of the MexEF-OprN efflux pump [365].
3.3. TCSs in Staphylococcus aureus
Virulence factor production in Staphylococcus aureus is largely under the control of the accessory gene regulator (agr) QS system (agrBDCA), the SaeRS and ArlRS QS systems, as well as the transcriptional regulators SarA and MgrA [308,366,367,368,369,370] (Figure 9). There are four agr groups, all of which exhibit bacterial interference [366,370,371]. Each agr type synthesizes a cyclic autoinducing peptide (AIP) with a distinct sequence that activates its cognate AgrC receptor and inhibits the activation of others [366,370]. The four Staphylococcus aureus AIPs are seven to nine amino acids long and all contain a thiolactone macrocycle, involving a conserved cysteine sulfhydryl group and R-carboxylate, and an N-terminal tail region [366,370].
The P2 operon in the agr locus encodes a polycistronic mRNA termed RNAII which is translated into four Agr proteins (AgrA-D) involved in the autoinduction circuit [370]. AgrD is the precursor of AIP which is proteolytically processed by the AgrB peptidase to generate a thiolactone intermediate. The intermediate is exported and further processed into mature AIP pheromone that activates the membrane-bound AgrC receptor histidine kinase, resulting in the phosphorylation and activation of the response regulator AgrA [366,370]. The phosphorylated AgrA activates the P2 promoter resulting in the upregulation of RNAII, thereby providing a feed-forward QS signaling circuit. In addition, ArgA activates the P3 operon encoding RNAIII, which is a pleiotropic regulator factor. RNAIII functions by base-pairing to the 5’-ends of virulence factor mRNAs, suppressing the synthesis of proteins involved in adhesion, while increasing those involved in invasion [372]. A portion of RNAIII is translated into δ-toxin. RNAIII upregulates the expression of alpha-hemolysin [373] and the global regulator mgrA [374], while represses the expression of coa (coagulase), spa (protein A), and the pleiotropic transcription factor rot (repressor of toxin), which is responsible for the repression of toxins [375,376].
AgrCA positively regulates various virulence factors such as hemolysins, proteases, nucleases, phenol-soluble modulins (PSMs), leukocidins, toxins, and capsular polysaccharides, that contribute to the invasive phenotype [308]. In addition, AgrCA upregulates the TCSs arlRS and saePQRS [308]. The activity of AgrA can be modulated by SarA and SarR [377]. SaeRS regulates the expression of various virulence factors including fibronectin-binding proteins, hemolysins, leukocidins, and coagulase that are important for the pathogenicity of Staphylococcus aureus [378,379].
Agr also represses the expression of apsRS which confers resistance to antimicrobial peptides such as human β-defensin-3, LL37, and bacteriocins (nisin A, nukacin ISK-1) [380]. ApsR regulates the dlt operon that adds alanine to teichoic acid in the cell wall and mprF (fmtC), which adds lysine to phosphatidylglycerol in cell membranes [381,382,383]. This leads to a reduced negative charge of the bacterial surface, and a consequently reduced binding of the positively charged antimicrobial peptides [381,382,383]. Since Agr expression is low during the early phase of bacterial growth, while high in the stationary phase, the susceptibility to antimicrobial peptides changes during cell growth with low susceptibility during the exponential phase and high susceptibility in the stationary phase [380,384].
3.4. Involvement of Two-Component Systems in Promoting Antibiotic Resistance
QS may affect antibiotic resistance by altering the expression of efflux pumps and β-lactamases, modulating the membrane structure, and promoting biofilm formation [31,302,385,386,387] (Table 2 and Section 4.1). Vice versa, efflux pumps may be important for QS and biofilm formation. For instance, the QS-regulated biofilm formation in Burkholderia pseudomallei was found to rely on the BpeAB-OprB efflux pump [388]. The autoinducers N-octanoyl-homoserine lactone (C8-HSL) and N-decanoyl-homoserine lactone (C10-HSL) of Burkholderia pseudomallei induced the expression of BpeAB-OprB, and BpeAB was required for acyl-homoserine lactone (acyl-HSL) production and optimal production of quorum sensing-controlled virulence factors such as siderophore and phospholipase C [388]. In analogy, reduced biofilm formation was observed in Escherichia coli mutants that do not express various genes associated with efflux pumps including emrD, emrE, emrK, acrD, acrE, and mftE [158].
The envelope stress responsive AmgRS TCS of Pseudomonas aeruginosa is activated following membrane damage caused by Zn ions and aminoglycosides [197,396]. The aminoglycoside-mediated activation of AmgRS results in the induction of mexXY and mexAB-oprM multidrug efflux operons, which confer aminoglycoside resistance [197,397]. The Zn-induced mexXY expression relies on the TCS ParRS [396]. Zinc also activates the TCS ColSR that promotes cell envelope-protective modifications, contributing to Zn tolerance [415].
Gram-negative bacteria survive harmful environmental stressors by modifying their outer membrane. This protection is often achieved by modifying the lipid A moiety of LPS. Various environmental stress stimuli can induce the addition of cationic components, such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine (pEtN) at the lipid A phosphate groups, which contribute to the stabilization of the outer membrane.
The TCS CprRS of Pseudomonas aeruginosa triggers the expression of the LPS modification arnBCADTEF operon upon exposure to cationic antimicrobial peptides [418]. The arnBCADTEF operon mediates the addition of the positively charged arabinosamine to the negatively charged lipopolysaccharides, thereby preventing the binding of cationic antimicrobial peptides to the lipopolysaccharides [418]. Since the membrane permeabilization activity caused by the antimicrobial peptides relay on their binding to LPS, the arabinosamine modification of LPS leads to drug resistance [418]. The arn operon is also induced by low Mg2+ concentration detected by the TCSs PhoPQ and PmrAB [452], and by cationic peptides that activate the TCS ParRS [449]. Extracellular DNA present in biofilms activates PhoPQ and PmrAB through chelating metal ions, thus inducing antimicrobial peptide resistance [471]. The activation of PhoPQ and PmrAB is also caused by extracellular DNA-mediated acidification of the biofilms [454]. The activation of PhoPQ and PmrAB resulted in resistance to aminoglycoside antibiotics which is caused by both aminoarabinose modification of lipid A and production of spermidine on the bacterial outer membrane which interacts electrostatically with the negative charges of the O-antigen [454,471]. Both modifications likely reduce the entry of the aminoglycoside into the bacteria [454,471]. DNA-enriched biofilms were 8-fold more tolerant to the antimicrobial peptides polymyxin B and colistin, and 64- to 128-fold more tolerant to the aminoglycosides gentamicin and tobramycin [472].
In Pseudomonas aeruginosa, the phosphoethanolamine modification is mediated by a pEtN transferase that is regulated by zinc ions via the ColRS TCS [415]. In Escherichia coli and Salmonella enterica, the pEtN transferase eptA is regulated by the PmrAB TCS [473]. Mutation in PmrAB in Acinetobacter baumannii showed a 30-fold increase in the transcription of pmrC, which encodes the lipid A phosphoethanolamine transferase [474]. In Salmonella, PhoP can activate pagB, which encodes a palmitoyltransferase that adds palmitic acid to lipid A [475]. In Salmonella enterica, the knockout of PhoPQ made the bacteria more susceptible to antimicrobial peptides by making their surface less rigid and more polarized [476].
The Cpx stress response mediated by the two-component sensor histidine kinase CpxA and the cytoplasmic response regulator CpxR confers resistance to aminoglycoside antibiotics [477], hydroxyurea [477], cationic antimicrobial peptides [420,423], β-lactams [211,403], and chlorhexidine [478], besides being implicated in virulence [479] and biofilm formation [480,481] (Figure 10). The Cpx TCS senses periplasmic or inner membrane protein misfolding and accumulation resulting in the upregulation of the periplasmic protease DegP and degradation of the misfolded proteins [482]. In addition, Cpx induces the expression of the protein folding factors dsbA, ppiA, cpxP, and spy [482]. The expression of Cpx-regulated genes was shown to be upregulated upon initial adhesion of Escherichia coli to abiotic surfaces, a response requiring the outer membrane lipoprotein NlpE [483]. The Cpx regulon is also upregulated by cell wall-acting antibiotics such as β-lactams [484] and cationic antimicrobial peptides [420] besides its induction by copper ions [485] and alterations in pH and osmolarity [211]. Activation of CpxRA by the aromatic metabolite indole stimulates mar transcription [423], which subsequently triggers the multidrug resistance cascade. The CpxRA TCS controls the expression of proteoglycan-modifying enzymes such as the LdtD (YcbB) transpeptidase which catalyzes unusual diaminopimelic acid (DAP)-DAP crosslinks [486] and mediates resistance to β-lactams [487]. In Salmonella, CpxRA upregulates the expression of the two N-acetylmuramoyl-L-alanine amidases encoded by amiA and amiC, resulting in bacterial resistance to protamine and the α-helical peptides magainin 2 and melittin [424]. CpxRA, together with the TCS EnvZ/OmpR, regulates the expression of the porins ompF and ompC in Escherichia coli [211,425].
In Staphylococcus aureus, the TCS GraRS was found to regulate resistance to cationic antimicrobial peptides and vancomycin [439]. The membranal receptor GraS senses cationic antimicrobial peptides, resulting in its autophosphorylation on histidine [439]. The GraS then phosphorylates the GraR regulator that upregulates the efflux pump vraFG that can pump out cationic antimicrobial peptides as well as vancomycin [439,442]. VraFG can also affect the expression of mprF, which attaches lysine to membrane phospholipids and dltABCD which adds D-alanine to cell wall teichoic acids, two processes that result in an increase in the net surface positive charges [439,488].
4. Biofilms
Biofilm formation is one of the main causes of the persistence of pathogenic bacteria associated with severe infections and outbreaks in hospitals. It is a universal phenomenon among microorganisms and is an important virulence factor that is responsible for the colonization of living tissues or medical devices and causes treatment failure due to decreased susceptibility to antimicrobial drugs and resistance to host defense mechanisms. The biofilms appear as complex three-dimensional structures where the bacteria are embedded in a network of extracellular polymeric matrices (EPS) composed of proteins, polysaccharides, alginates, lipids, teichoic acids, extracellular DNA (eDNA), and other organic compounds secreted by the bacteria or absorbed from the surrounding environment. The EPS can account for over 90% of the biofilm biomass [2,489]. The EPS functions as a barrier and boundary between the microbial community and the external environment, and it plays a central role in bacterial attachment. Additionally, eDNA released from the lysis of a subpopulation of bacterial cells is involved in the attachment, aggregation, and stabilization of the biofilms [490]. eDNA may even facilitate adhesion to highly hydrophobic surfaces [491]. Some autolysins are important for the release of eDNA and the consequent biofilm formation [490,492,493,494,495]. The biofilms have a high water content that allows the flow of nutrients required for bacterial survival within the biofilms [4].
Biofilm formation is characterized by four major stages that act in a cyclic mode [2,8,496,497,498]: (1) an initial reversible attachment to a biotic or abiotic surface, followed by an irreversible binding to the surface; (2) maturation stage where replication of the bacteria forms a microcolony, accompanied by the production of EPS and other components of the extracellular matrix surrounding the microcolony; (3) adhesion of other bacteria to the glycocalyx composed of EPS and other components, thus increasing the complexity and depth of the biofilm that can reach multiple layers of more than 100 μm; (4) release of some of the bacteria from the mature biofilm, leading to the dispersion of the bacteria to other locations thus generating infection with potentially new biofilm formation. During biofilm maturation, canals are formed in the biofilm structure. These allow gradient-based passage of nutrients and signaling molecules, favoring organized agglomeration and differentiation of cells based on their metabolic state [2].
The initial attachment can be active or passive depending on microbial factors such as motility and expression of adhesins and is affected by the kind of surface [499]. The glycocalyx, which is composed of glycoproteins and polysaccharides, contributes to the maturation of the biofilms through electrostatic and hydrogen bonds between the EPS and the surface [499]. Not only the complex polysaccharides but also extracellular DNA contribute to the structure of the matrix and enable cell–cell and cell–surface interactions [500]. The bacteria might also produce factors that induce tissue damage, thereby favoring their subsequent adhesion [501]. The EPS is important for the development of a microenvironment that allows microbial cell–cell interactions and communication, and some of its components may serve as a reservoir of metabolic substances, nutrients, and energy for the biofilm-embedded microbes [2]. Enzymes that can degrade the EPS polymers play an important role in the biofilm life cycle. They provide carbon and energy during starvation and cause biofilm degradation during detachment and dispersal [496,502]. The bacteria in the outer biofilm layers display active metabolism, while those in the deeper layers of the biofilm where hypoxia prevails, show reduced metabolism and have entered a sessile, dormant state [4].
4.1. Regulation of Biofilm Formation
Biofilm formation is induced by different factors including changes in the environmental conditions including oxidative stress, alterations in nutritional and metabolic cues, low pH, starvation, heavy metals, host-derived signals, toxic compounds, QS signals, and subinhibitory concentrations of antimicrobials [20,503,504,505,506,507,508,509,510,511,512]. For instance, biofilm formation of Salmonella typhimurium is induced by acidic stress and bile salts under oxygen-limiting conditions in the stomach and the small intestine [513]. Biofilm formation is affected by the properties of the biotic or abiotic surfaces [4,499]. Within the biofilms, the microbes coordinate their behavior for promoting growth and producing EPS [489,514].
4.1.1. Induction of Biofilm Formation by Low Antibiotic Concentrations
Various antibiotics at subinhibitory concentrations can induce biofilm formation [263,510,512,515,516,517,518,519,520]. The cell wall antibiotic-induced biofilm formation of Enterococcus faecalis was associated with increased cell lysis, increased extracellular DNA levels, and an increased density of bacteria within the biofilm [510]. In Staphylococcus aureus, the β-lactam antibiotics induce extracellular DNA release that was dependent on the autolysin Atl [515]. The mupirocin-induced biofilm formation of Staphylococcus aureus was dependent on the upregulation of the CidA holin that was associated with the increased production of extracellular DNA [520]. Hoffman et al. [516] observed that aminoglycoside antibiotics could induce biofilm formation of Pseudomonas aeruginosa through a mechanism that depends on the aminoglycoside response regulator (arr). The arr gene encodes for an inner membrane phosphodiesterase whose substrate is cyclic di-guanosine monophosphate (c-di-GMP), a second messenger that regulates cell-surface adhesiveness [516,517] (see Section 4.1.3). Chloramphenicol and erythromycin induce the expression of the capsular exopolysaccharide in Acinetobacter baumannii through a mechanism that depends on the TCS BfmRS [518].
Azithromycin, on the other hand, reduces biofilm formation of Pseudomonas aeruginosa and inhibits QS-regulated virulence factors such as autoinducer production, pyocyanin production, and swarming [521,522,523]. Azithromycin downregulates the expression of gacA [521], which mediates the switch between the motile and biofilm lifestyles of Pseudomonas aeruginosa [524]. The involvement of GacA in biofilm formation will be further discussed in Section 4.4.
4.1.2. Involvement of Two-Component Systems in Biofilm Formation
The QS cell-to-cell communication among bacteria facilitates the formation of specialized biofilm structures and causes alterations in the expression of surface molecules such as adhesins that promote adhesion [4,5,301,335,503,507,525,526,527,528,529] (Table 3). The QS-regulated biofilm formation affects both bacterial pathogenesis and resistance to antibiotics [526,527,530,531]. The dependency of biofilm induction on cell density varies between the bacterial species. For instance, in Vibrio cholerae, the biofilm-related genes are induced at low cell density, whereas biofilm-related genes in Pseudomonas aeruginosa are expressed at high cell density [326,505,532].
LuxS, which is responsible for AI-2 synthesis, is one of the first autoinducer synthetases that was demonstrated to affect biofilm formation [530]. It might either reduce or promote biofilm formation depending on the bacterial species [344,530,533,534,535,536,537] (Table 3). For instance, in Vibrio strains AI-2 increases biofilm formation and motility [290,338]. In Staphylococcus epidermidis, the luxS mutant formed a thicker and more compact biofilm compared to the wild-type strain [533]. LuxS appears to repress biofilm formation in these bacteria through transcriptional regulation of the ica gene locus that is responsible for PIA exopolysaccharide production [533]. Similarly, in Staphylococcus aureus, LuxS seems to prevent biofilm formation by activating the transcription of icaR, a repressor of the ica operon [538]. In Salmonella typhimurium, AI-2 induces the transcription of the lsrACDBFGE operon which, among others, encodes for the lsr ATP-binding (ABC) transport system involved in the uptake of AI-2 [539]. LuxS is also responsible for virulence gene expression in Salmonella typhimurium [540], and in the absence of luxS and AI-2, biofilm formation was impaired in these bacteria [536]. Exogenously added AI-2 increased Escherichia coli biofilm formation among others by upregulating adhesin antigen 43 and curli fibers [537,541,542].
Table 3Examples of regulatory factors including two-component systems (TCSs) affecting biofilm formation.
| Biofilm |
Function | Species | Reference |
|---|---|---|---|
| Agr |
|
Staphylococcus aureus | [370] |
| AlgD-A |
|
Pseudomonas aeruginosa | [509,543,544] |
| AlsSD |
|
Staphylococcus aureus | [545,546] |
| ArgR |
|
Staphylococcus aureus | [547,548] |
| ArlRS |
|
Staphylococcus aureus | [549,550,551,552] |
| AtlA/AtlE |
|
Staphylococcus aureus, |
[492,493,553] |
| BasSR |
|
Escherichia coli | [554] |
| BfiRS |
|
Pseudomonas aeruginosa | [555,556,557] |
| BfmRS (RtsAB) |
|
Acinetobacter baumannii, Pseudomonas aeruginosa | [518,558,559,560,561] |
| cAMP-CRP |
|
Escherichia coli, |
[562,563,564,565] |
| CidABC |
|
Staphylococcus aureus | [495,546,566] |
| c-di-GMP |
|
Pseudomonas aeruginosa | [508,517,567,568,569,570,571] |
| CodY |
|
Staphylococcus aureus | [572,573,574] |
| CqsA |
|
Vibrio harveyi | [336] |
| CpxRA |
|
Escherichia coli, |
[575] |
| CreBC (BlrAB) |
|
Pseudomonas aeruginosa | [426,576] |
| CsgD |
|
Escherichia coli, |
[577,578,579,580] |
| DltA |
|
Staphylococcus aureus | [581] |
| FsrBDC |
|
Enterococcus faecalis | [582,583,584] |
| GacSA |
|
Pseudomonas aeruginosa, |
[507,559,585,586,587,588] |
| GraRS |
|
Staphylococcus aureus | [441,589] |
| HapR |
|
Vibrio cholerae | [335,504] |
| LadS |
|
Pseudomonas aeruginosa | [507,585,590] |
| LasR/LasI |
|
Pseudomonas aeruginosa | [296,505,509,591] |
| LecA |
|
Pseudomonas aeruginosa | [592] |
| LrgAB |
|
Staphylococcus aureus | [289,593] |
| LuxS |
|
Salmonella species, |
[525,530,538,541,594,595,596] |
| LytA |
|
Streptococcus pneumoniae | [597] |
| LytSR |
|
Staphylococcus aureus | [598,599] |
| MgrA |
|
Staphylococcus aureus | [374,398,549,550,552,600] |
| MifRS |
|
Pseudomonas aeruginosa | [557,601] |
| QseBC |
|
Escherichia coli, |
[249,541,602,603,604] |
| PA1161 |
|
Pseudomonas aeruginosa | [605] |
| PilSR |
|
Pseudomonas aeruginosa | [606,607] |
| (p)ppGpp |
|
Escherichia coli, |
[570,608,609,610,611,612,613] |
| PprAB |
|
Pseudomonas aeruginosa | [614,615] |
| Rbf |
|
Staphylococcus aureus, |
[616,617,618] |
| RcsCDB |
|
Escherichia coli, |
[484,619,620,621,622,623,624] |
| RetS |
|
Pseudomonas aeruginosa | [524,625] |
| RhlR/RhlI |
|
Pseudomonas aeruginosa | [509,626,627] |
| RocS1A1R |
|
Pseudomonas aeruginosa | [628,629] |
| Rot |
|
Staphylococcus aureus | [630] |
| RpoS |
|
Escherichia coli, |
[578,631,632,633,634,635,636,637] |
| SadARS |
|
Pseudomonas aeruginosa | [638] |
| SaeRS |
|
Staphylococcus aureus | [639,640] |
| SagS |
|
Pseudomonas aeruginosa | [230,555,568,641,642,643,644] |
| SarA |
|
Staphylococcus aureus | [645,646,647,648] |
| SarX |
|
Staphylococcus aureus, |
[616,649,650,651] |
| SdiA |
|
Escherichia coli, |
[652,653,654] |
| SigB |
|
Staphylococcus aureus | [655] |
| SrrAB |
|
Staphylococcus aureus | [549] |
| TcaR/IcaR |
|
Staphylococcus aureus | [656,657,658] |
| VraSR |
|
Staphylococcus epidermidis | [467] |
4.1.3. Role of Cyclic di-GMP (c-di-GMP) in Biofilm Formation
Various bacterial species, especially Gram-negative bacteria such as Pseudomonas aeruginosa, Salmonella enterica, Escherichia coli, and Vibrio cholerae, use the secondary metabolite c-di-GMP signaling to regulate biofilm formation [659,660,661,662]. c-di-GMP regulates the transition from planktonic to biofilm state [662]. In general, low intracellular c-di-GMP levels are associated with motility and a planktonic lifestyle, whereas high c-di-GMP levels are associated with biofilm formation and sessility [507,517].
c-di-GMP modulates several aspects of biofilm formation, including flagella rotation, type IV pili retraction, EPS production, surface adhesin expression, resistance to antimicrobial drugs and other stress responses, secondary metabolite production, and biofilm dispersion [517,659] (Figure 11; and Section 4.4). In addition, c-di-GMP affects many other bacterial functions such as cell division, type III secretion, RNA modulation, stress responses, and virulence [663]. Changes in c-di-GMP levels are sensed by c-di-GMP receptor proteins and riboswitch RNAs which propagate the downstream signaling cascade [664,665]. In Pseudomonas aeruginosa, c-di-GMP is required for the synthesis of the extracellular polysaccharides Psl and Pel [666], affects the expression of the extracellular matrix adhesion protein CdrA that interacts with Psl and Pel [666,667], and modulates the production of alginate [668].
The c-di-GMP level is controlled by enzymes that synthesize c-di-GMP (e.g., diguanylate cyclases (DGCs) carrying a GGDEF active site motif) and enzymes that degrade the molecule (e.g., c-di-GMP phosphodiesterases (PDEs) carrying either EAL or HD-GP domains) [662]. The Pseudomonas aeruginosa genome encodes one of the highest numbers of DGCs and PDEs: 18 GGDEF, 5 EAL, 16 GGDEF/EAL, and 3 HD-GYP predicted proteins [517]. Upon contact of Pseudomonas aeruginosa with a surface, the membrane-bound receptor, WspA, becomes activated and triggers c-di-GMP production by the DGC WspR [669]. c-di-GMP, in turn, downregulates the flagellum motility machinery, thereby forcing the bacteria into a sessile growth mode [669].
4.1.4. Role of Non-Coding RNAs (ncRNAs) or Small Regulatory RNA (sRNA) in Regulating Biofilm Formation
The multicellular adhesive McaS sRNA of Escherichia coli interacts with mRNAs encoding master transcription regulators of curli and flagella synthesis, resulting in their respective downregulation and upregulation [276]. In Escherichia coli, McaS activates the synthesis of the exopolysaccharide β-1,6 N-acetyl-D-glucosamine (PGA) by binding and blocking the global RNA-binding protein CsrA, which negatively regulates pgaA translation and positively controls the flagellar master flhDC operon expression [276,578]. Ectopic McaS expression leads to the induction of diguanylate cyclases that are repressed by CsrA [276].
The bacterial 3’UTR-derived non-coding RNA RibS was found to affect the biofilm formation of Salmonella enterica serovar Typhi [271]. RibS is formed by RNase III-mediated cleavage of the 3’UTR of riboflavin synthase subunit alpha mRNA RibE [271]. Overexpression of RibS promotes biofilm formation by increasing the expression of the cyclopropane fatty acid synthase gene cfa [271]. The expression of cfa is also regulated by the sRNAs RydC, ArrS, and CpxQ [670]. Both RydC and ArrS mask the RNaseE cleavage site in the cfa mRNA 5’-UTR, resulting in the upregulation of cfa [670]. CpxQ binds to a different site of the cfa mRNA 5’UTR, resulting in the repression of cfa [670].
The σS-dependent sRNA SdsR was shown to regulate biofilm formation in Salmonella by activating csgD and curli expression and downregulating the ompD porin [578]. In Escherichia coli, SdsR inhibits flhDC expression [578].
The small non-coding RNA RsaE affects extracellular matrix composition in Staphylococcus epidermidis biofilm [671]. RsaE interacts with the antiholin lrgA mRNA, thereby facilitating bacterial lysis and eDNA release [671]. Moreover, RsaE augments PIA-mediated biofilm matrix production [671]. The long non-coding RNA IcaZ prevents icaR translation, thereby relieving the repression of icaADBC transcription with a consequent increase in PIA production [672].
The small non-coding RsmW RNA in Pseudomonas aeruginosa upregulates biofilm formation by binding to the RNA-binding regulator RsmA [673]. RsmA represses the type VI secretion system, exopolysaccharide production, and biofilm formation [674,675]. The involvement of RsmY and RmsZ in regulating RsmA will be discussed in Section 4.4.
4.2. Biofilm Formation by Vibrio cholerae
The extracellular matrix of Vibrio cholerae, the causative agent of cholera, is composed of Vibrio polysaccharides (VPS) and three major matrix proteins, RbmA, RbmC, and Bap1 involved in cell–cell and cell–surface adhesion [676]. Several transcriptional regulators and alternative sigma factors control the biofilm formation in Vibrio cholerae. Among them, VpsR and VpsT are considered master regulators of biofilm formation which positively regulate VPS production [677,678]. Both VpsR and VpsT respond to c-di-GMP by inducing the transcriptional switch toward biofilm-regulated genes [678,679,680].
4.3. Biofilm Formation by Escherichia coli
The QseBC TCS of Escherichia coli was found to promote biofilm formation in dairy cows that suffered from mastitis by upregulating the transcription of the biofilm-associated genes bcsA, csgA, fliC, motA, wcaF, and fimA, and conferred antibiotic resistance by upregulating the transcription of the efflux pump-associated genes marA, acrA, acrB, acrD, emrD, and mdtH [249]. The BasSR TCS promotes biofilm formation in avian pathogenic Escherichia coli by upregulating the expression of biofilm- and virulence-related genes, including ais, entC, opgC, gtcE, and fepA [554]. Moreover, the CpxRA TCS, which senses membrane stress and recognizes misfolded proteins, is required for proper biofilm formation, adherence, motility, and the production of type 1 fimbriae [681].
4.4. Biofilm Formation by Pseudomonas aeruginosa
The biofilms of Pseudomonas aeruginosa are characterized by exopolysaccharides (EPS) such as Psl, Pel, and alginate intermingled with proteins, rhamnolipids, membrane vesicles, and eDNA [682,683]. The rhamnolipid biosurfactants are required for the initial stage of microcolony formation, the formation of the mushroom-shaped microcolonies, the maintenance of channels between multicellular structures, and contribute to biofilm dispersal [682,683]. The intercalation of the redox active virulence factor pyocyanin with eDNA contributes to the stabilization of the Pseudomonas aeruginosa biofilm architecture [684]. Moreover, the flagellum is considered a central component of the biofilm formation of Pseudomonas aeruginosa since it provides the mobility needed to actively approach a surface [301]. The type IV pili play a role in surface attachment and colonization [301]. The Cup fimbriae were also found to contribute to the attachment to both abiotic and biotic surfaces, besides providing protection against the recognition by the immune system [301].
The production of the virulence factors rhamnolipids and pyocyanin, and the release of eDNA and membrane vesicles, as well as biofilm development, are controlled by the QS two-component system [296,514]. The QS also elicits a global metabolic rewiring in Pseudomonas aeruginosa which is caused by a combination of direct transcriptional alteration of metabolism-associated genes mediated by the QS system and indirectly by global metabolic readjustment as a result of the general and QS-dependent stress responses [685].
In Pseudomonas aeruginosa, small cationic polyamines such as putrescine as well as its biosynthetic precursors L-arginine and agmatine ((4-aminobutyl)guanidine), promote biofilm formation and confer resistance to environmental stress stimuli [508,517,686]. Both putrescine and L-arginine increase the intracellular c-di-GMP levels [686]. One of the diguanylate cyclases in Pseudomonas aeruginosa is SiaD which is co-transcribed with siaA/siaB/siaC from the siaABCD operon. The siaABCD encodes a signaling network regulating biofilm and aggregate formation by modulating the enzymatic activity of SiaD [687]. SiaC interacts with SiaD to promote its diguanylate cyclase activity, thus promoting c-di-GMP synthesis [687]. The interaction of SiaC with SiaD is facilitated by dephosphorylation mediated by the inner membrane-associated Ser/Thr SiaA phosphatase, while it is prevented when phosphorylated by the SiaB protein kinase [687]. SiaA is activated by external stress stimuli such as sodium dodecyl sulfate [687].
Biofilm formation in Pseudomonas aeruginosa is, among others, regulated by the two QS systems LasI/LasR and RhlR/RhlI that are expressed at both early and late biofilm phases [688,689]. A lasI mutant forms flat and undifferentiated biofilms that were sensitive to sodium dodecyl sulfate [505]. Pseudomonas aeruginosa rhlA mutants that are deficient in the synthesis of biosurfactants were not capable of forming microcolonies in the initial phase of biofilm formation and were defective in migration-dependent development of mushroom-shaped multicellular structures in the later phase of biofilm formation [682]. The Rhl system regulates the expression of pyocyanin and rhamnolipids that are responsible for the deposition of extracellular DNA which is an important component in the early and late biofilm developmental stages. Additionally, the PqsE thioesterase, which is part of the 2-alkyl-4-quinolone biosynthesis gene cluster pqsABCDE, plays a role in the production of pyocyanin, rhamnolipids, and lectin A [690].
The GacSA TCS in Pseudomonas aeruginosa increases the expression of the exopolysaccharides Pel and Psl by upregulating the expression of two small regulatory RNAs, rsmY and rsmZ [301]. RsmY and RsmZ sequester the translational repressor RsmA thus allowing translation of target mRNAs such as the exopolysaccharides pel and psl, required for biofilm formation [301,691] (Figure 12A). RsmA increases the expression of the type III secretion system (T3SS) while repressing the expression of the type VI secretion system (T6SS) [625,692]. The activity of GacS is activated by the hybrid histidine kinase LadS [585], while antagonized by the hybrid sensor kinase RetS [524]. The activity of RetS is repressed by the hybrid sensor kinase PA1611, which positively regulates biofilm formation by upregulating rsmY and rsmZ [605]. The expression level of PA1611 is increased during the transition between acute and chronic infection and mediates the transition to the biofilm state [605]. A retS mutant showed elevated levels of c-di-GMP, increased biofilm formation, and a shift in type III and type VI secretion systems that were dependent on c-di-GMP [625]. The siaABCD responsible for c-di-GMP production is repressed by RsmA [693], thereby generating a feedback loop (Figure 12A). GacSA also positively regulates the transcription of the QS components lasR and rhlR in Pseudomonas aeruginosa [296]. A ΔgacA mutant showed a 10-fold reduction in the ability to form biofilms [588]. The ΔgacS strain was hypermotile, produced a reduced amount of acyl-homoserine lactones, showed impaired biofilm maturation, and was more sensitive to certain antibiotics (e.g., tobramycin, ceftriaxone, oxacillin, piperacillin, and rifampicin) in comparison to the parental strain [694].
Other TCSs involved in the biofilm formation of Pseudomonas aeruginosa include SagS, BfiRS, BfmRS, and MifRS [301,556,557]. SagS, BfiRS, BfmRS, and MifRS are sequentially phosphorylated during biofilm formation [557] (Figure 12B). Inactivation of either of these components arrests biofilm formation at distinct developmental stages [502,555,556,557]. Biofilms formed by ΔsagS and ΔbfiS mutants are arrested at the irreversible attachment stage, while biofilms formed by ΔbfmR and ΔmifR mutants are arrested at the maturation-1 and maturation-2 stages of biofilm development, respectively [502,555,556,557]. SagS enables the switch from the planktonic state to the sessile, biofilm state, through activation of the TCS BfiRS [555,556,641]. BfiRS represses the rsmYZ expression levels which seem to be a necessary step for future maturation of Pseudomonas aeruginosa biofilm [556]. SagS is also required for the biofilm-associated resistance to antibiotics through BrlR-mediated upregulation of efflux pumps such as mexAB-oprM and mexEF-oprN [569,644]. The BrlR expression was dependent on sufficient levels of c-di-GMP [569]. BmfRS regulates biofilm maturation [561], while MifRS modulates microcolony formation [695]. The loss of biofilm biomass in the ΔbmfR mutant might be related to increased cell death [696].
The fimbrial cupB and cupC genes are regulated by the roc1 locus that encodes one sensor kinase (RocS1) and two response regulators (RocA1 and RocR) [301]. This cluster has also been termed sadARS and has been documented to positively regulate biofilm formation while repressing type III secretion genes [638]. Nonpolar mutations in any of the sadARS genes result in biofilms with an altered mature structure, but without defects in growth or early biofilm formation, swimming, or twitching motility [638]. Mutations in type III secretion genes resulted in strains with enhanced biofilm formation [638]. Type III secretion genes including pcrV are negatively regulated by c-di-GMP [697]. Of note, RocR contains an EAL motif with a phosphodiesterase activity that degrades c-di-GMP [629]. RocA2 was found to repress the expression of the mexAB-oprM efflux pump [698]. The RocS1A1R system seems to be counterintuitive by providing a signal cascade that promotes biofilm formation via Cup fimbriae and simultaneously increases the sensitivity to antibiotics by repressing a multidrug efflux pump. This could be associated with the fitness cost of this efflux pump in a biofilm environment [301].
4.5. Biofilm Formation by Staphylococcus Species
The biofilms of Staphylococcus aureus can be classified into ica-dependent and ica-independent biofilms. The ica-dependent biofilms are associated with exopolysaccharide intercellular adhesin/poly-N-acetylglucosamine (PIA/PNAG; product of the ica operon) involved in intercellular adhesion [699]. These polysaccharides are encoded by the icaADBC operon. The ArcC-type transcriptional regulator Rbf activates the icaADBC operon and PIA production in Staphylococcus epidermidis by preventing the transcription of the SarR repressor [617]. The ArlRS TCS regulates PNAG synthesis in Staphylococcus aureus by repressing icaR, a transcriptional repressor of the icaADBC operon [549]. The arl mutant of Staphylococcus aureus showed reduced catheter colonization [549].
The ica-independent biofilms have a proteinaceous matrix and are more frequently found in MRSA isolates [700,701]. These biofilms involve fibrinogen and fibronectin-binding proteins FnBPA and FnBPB, which are LPXTG-containing proteins anchored to peptidoglycan [700,702,703]. Loss of sortase (sarA), which anchors LPXTG-containing proteins to peptidoglycan, reduced the MRSA biofilm phenotype [700]. Other proteins involved in ica-independent biofilm formation include Staphylococcus aureus surface proteins C and G (SasC and SasG), extracellular adherence protein (Eap), biofilm-associated protein (Bap), fibronectin-binding proteins (FnBPs), clumping factor B (ClfB), and Staphylococcus protein A (Spa) [704,705,706,707,708,709].
In Staphylococcus aureus, the accessory gene regulator (arg) QS system is involved in regulating biofilm formation [370]. Silencing the agr system strengthens biofilm formation [533]. The increased biofilm thickness of the agr mutant is thought to be due to the inability of the cells to detach from the mature biofilm [533]. AgrB, which is associated with the secretion of virulence factors, promotes biofilm dispersion through increased production of the Aur metalloproteinase and the SplABCDEF serine proteases [528,710]. The Arg-mediated detachment of bacteria from the biofilm restored sensitivity to rifampicin [710]. Another reason for the increased biofilm formation of agr mutants might be the AgrA-mediated regulation of the phenol-soluble modulin (PSM) operon. PSMs have surfactant-like properties that are involved in biofilm dispersion [711]. Other systems in Staphylococcus aureus regulating virulence genes and biofilm formation include the TCSs ArlRS, SaeRS, SrrAB, and GraRS [367,368,441,549,712] (Table 3).
During the biofilm formation of Staphylococcus aureus, a small subpopulation undergoes lysis to provide extracellular DNA that glues together the extracellular matrix [593,713,714]. This process is regulated by the holin-like CidABC and the anti-holin-like LrgAB systems [495,593,715]. CidA, which regulates the activities of murein hydrolases, promotes genomic DNA release and biofilm formation [495,715]. LrgAB, which is regulated by the LytSR TCS [289], inhibits CidA-mediated lysis [593]. CidA and LrgA are membrane-associated proteins that form heteromers with disulfide bonds formed between cysteine residues [716]. An lrgAB mutant exhibited increased biofilm formation and matrix-associated extracellular DNA [593]. The murein hydrolase AtlA is important for the initial adhesion of Staphylococcus aureus to a surface [553]. AtlA is also required for cell division, cell wall turnover, and bacterial lysis [553].
4.6. Biofilm Formation by Klebsiella pneumoniae
In Klebsiella pneumoniae, some virulence-related genes are involved in biofilm formation. These include the cps gene cluster responsible for capsule formation [717], the fimA and mrkA genes involved in type 1 and type 3 fimbriae formations [718], wbbM, which encodes an enzyme involved in the biosynthesis of the O-antigen of LPS [719], wzm involved in the transport of LPS [719], luxS of the type 2 QS regulatory system [525], and the pgaABCD operon responsible for the synthesis and translocation of the poly-β-1,6-N-acetyl-D-glucosamine (PGA) adhesin [720]. The RcsAB TCS regulates the biosynthesis of capsular polysaccharides by upregulating the gene galF [721]. Type 1 fimbriae mediate adherence to many types of epithelial cells, while type 3 fimbriae can bind to the extracellular matrix of urinary and respiratory tissues [722]. The luxS mutant could form mature biofilms but had a reduced ability to develop microcolonies, especially during the early stages of biofilm formation [525]. PgaC is involved in bile salt-induced biofilm formation [720]. The OxyR transcription factor upregulates the defense mechanisms against oxidative stress, bile salt, and acid stresses, and is important for biofilm formation and the production of types 1 and 3 fimbriae [723].
4.7. Antibiotic Resistance of Biofilm-Embedded Bacteria
Biofilm formation by pathogens is a major contributor to antibiotic resistance and treatment failure [20,724,725,726,727,728]. The EPS surrounding the biofilm-embedded bacteria protects the cells from adverse and disruptive environmental conditions. The biofilms can increase microbial tolerance to dehydration [729], radiation [729], extreme temperature and pH [729], osmotic stress, nutrient deficiency, metal toxicity, and antibiotics [8,724,730,731,732].
Bacteria embedded in biofilms are often more resistant to antimicrobial agents than planktonic growing cells [153,503,724,727,731,732,733,734]. There are several explanations for this phenomenon. The biofilms are highly persistent and protected from the immune system as well as adverse conditions such as antibiotics owing to their specialized structures [13,14,104]. Within the biofilm, the bacteria adapt to environmental anoxia and nutrient limitations, showing an altered metabolism and altered gene expression profile, concomitant with lower metabolic activity, reduced cell proliferation, and increased nutrient sequestration [1,13,14]. In addition, biofilm growth is associated with an increased level of mutations [14], and the proximity of the biofilm-embedded cells facilitates the horizontal transfer of resistance genes between the bacteria [20,727,735]. The secretion of β-lactamase from a biofilm-embedded bacteria into the biofilm matrix can prevent the β-lactam antibiotics to act on a neighboring cell even if the latter does not produce the enzyme [727]. Thus, antibiotic resistance can be passively conferred.
Bacterial metabolites can also affect the response to antibiotics [727]. For instance, indole produced by the metabolism of tryptophan can shift the antibiotic sensitivity profiles of neighboring organisms [727]. Indole induces the expression of drug transporters such as acrD, acrE, cusB, emrK, mdtA, mdtE, and yceL in Escherichia coli [212]. The induction of acrD, and mdtA by indole is mediated by the BaeSR and CpxAR TCSs [212]. Escherichia coli-produced indole protects Salmonella Typhimurium from ciprofloxacin by activating OxyR-regulated genes that confer protection from oxidative stress [736]. Another example of cross-species adaptive resistance is the interaction between Staphylococcus aureus and Candida albicans hyphae, which leads to resistance of Staphylococcus aureus to miconazole and vancomycin [737,738].
4.7.1. Prevention of Antibiotic Penetration through the Biofilm
The EPS enwrapping the bacteria in the biofilm are less penetrable for many antibiotic drugs (e.g., ampicillin), although some can diffuse through the biofilm matrix (e.g., ciprofloxacin) [733,739]. The negatively charged polysaccharides (especially the Pel polysaccharide and alginate of Pseudomonas aeruginosa) can effectively sequestrate the positively charged aminoglycoside-class of antibiotics such as tobramycin, thus preventing them from penetrating the deeper layers of the biofilm [739,740]. This property of EPS also makes the biofilm-embedded bacteria tolerant to metals such as zinc, copper, and lead [741].
Additionally, the extracellular DNA (eDNA) released to the extracellular matrix of the biofilms has been shown to neutralize the activity of antimicrobial drugs such as tobramycin and antimicrobial peptides, through its cationic chelating properties [454,742]. The eDNA through chelating cations such as magnesium ions forms a cation-limited environment that results in the induction of the PhoPQ and PmrAB TCSs in Pseudomonas aeruginosa [472]. These TCSs regulate cationic antimicrobial peptide resistance by upregulating the PA3552-PA3559 operon [472]. The DNA-induced expression of PA3552-PA3559 results in up to a 2560-fold increase in the resistance to cationic antimicrobial peptides and a 640-fold increase in the resistance to aminoglycosides [472]. Wilton et al. [454] observed that the aminoglycoside resistance is caused by aminoarabinose modification of lipid A and the production of spermidine on the outer membrane of the bacteria, both contributing to reduced uptake of aminoglycosides by the bacteria. The addition of L-arginine or sodium bicarbonate that neutralizes the acidic environment caused by eDNA could sensitize Pseudomonas aeruginosa to aminoglycosides [454].
The release of eDNA was found to be mediated by the Twin-arginine translocation Tat factor, which acts downstream to the PQS TCS in Pseudomonas aeruginosa [743]. tat mutants of Pseudomonas aeruginosa exhibit reduced eDNA release, defective biofilm architecture, and enhanced susceptibility to tobramycin [743]. In addition, the tat mutants showed reduced production of pyocyanin, rhamnolipid, and membrane vesicles that were associated with deficient expression of Rieske iron-sulfur subunit of the cytochrome bc1 complex involved in electron transfer and energy transduction [743].
4.7.2. Antibiotic Tolerance Due to Low Metabolic State of Biofilm-Associated Bacteria
Since the biofilm is a multilayered community of bacteria, nutrient and oxygen gradients are formed from the outer part to the inner part of the biofilms, resulting in metabolically versatile bacterial communities [2,744]. Different bacterial subpopulations showing distinct metabolic activities evolve within the biofilm depending on their spatial localization [745]. Both nutrient sparsity and hypoxia result in a decreased metabolic activity and growth rate of the bacteria in the biofilm core [746]. The low metabolic activities and slow growth rates of the sessile biofilm-associated bacteria and persister cells make them tolerant to antibiotics that rely on cell division (e.g., ciprofloxacin, tobramycin, tetracycline, penicillin) [610,747,748,749,750,751]. Additionally, conditions with nutrient limitations induce antibiotic tolerance in bacteria, which is associated with reduced levels of oxidative stress and depends on the SOS response [752,753]. Some of the dormant bacterial variants develop into antibiotic-tolerant persister cells that can regain cell proliferation when the therapy is withdrawn [41]. The persister subpopulation is, among others, controlled by stress signaling pathways such as the general stress response or the SOS response, in conjunction with the second messenger (p)ppGpp and the toxin–antitoxin modules [41]. The MazEF toxin–antitoxin system is thought to be responsible for biofilm-associated antibiotic resistance and the reduced metabolism resulting in the appearance of persister cells [754,755]. MazF is an endoribonuclease that cleaves single-stranded ACA sequences with consequent translational inhibition, and MazE is an antitoxin that antagonizes MazF [756]. The persistent cells are responsible for chronic infections as they tolerate antibiotics and escape the immune system.
4.7.3. Antibiotic Tolerance Due to Altered Chemical Microenvironment within the Biofilm
The high-affinity quinol oxidase cytochrome bd encoded by the cydABX operon which is induced under hypoxic conditions and exhibits high oxygen affinity is expressed at elevated levels within Escherichia coli biofilms and plays a role in maintaining the biofilm structure [744]. It is required for aerobic respiration under hypoxic conditions [744], and bacteria lacking cytochrome bd showed reduced expression of EPS and increased sensitivity to exogenous stress stimuli such as oxidative and nitrosactive stress [744]. The latter protection might be related to its quinol peroxidase activity [757]. Further studies show that cytochrome bd promotes antibiotic tolerance in Escherichia coli biofilms by promoting the proton-mediated efflux of noxious chemicals through the RND tripartite export proteins [758]. Deletion of cytochrome bd increased the susceptibility of biofilm-embedded Escherichia coli to several antibiotics including aminoglycosides, β-lactams, and fluoroquinolones [758].
4.7.4. Activation of Protective Stress Responses
Environmental stress stimuli such as decreased nutrition, lack of oxygen, and lower pH induce stress-response genes including sigma factors that protect the bacteria from antibiotics, host immune factors, and environmental toxins [14,15,759]. For instance, biofilm-associated Pseudomonas aeruginosa expresses the gene ndvB which encodes a glycosyltransferase that catalyzes the synthesis of periplasmic β-(1→3)-cyclic glucans. The glucans are thought to promote aminoglycoside resistance by sequestering the antibiotics (e.g., tobramycin) in the periplasm away from their cellular target [18]. The expression of ndvB in biofilms is dependent on the stationary-phase sigma factor RpoS [759] which is the master regulator of general stress responses [760]. Blocking the alternative sigma factor RpoN (σ54), which regulates many virulence factors, increased the susceptibility of Pseudomonas aeruginosa to β-lactam antibiotics [761].
4.7.5. Altered Expression of Antibiotic-Resistant Genes in Biofilm-Embedded Bacteria
When Pseudomonas aeruginosa biofilms are exposed to β-lactam antibiotics or colistin, various resistance mechanisms are induced such as increased expression of β-lactamase [762,763] and the production of modified lipopolysaccharides that make the bacteria resistant to colistin and other polymyxin antibiotics [764]. Polymyxins are cationic antimicrobial peptides that target Gram-negative bacteria through electrostatic interactions with lipid A and core phosphates of LPS. The resistance to these antibiotics is caused by modification of the lipopolysaccharides through the addition of L-4-aminoarabinose (L-Ara4N) and phosphoethanolamine (PEtN) [764]. These modification systems are regulated by complex networks of two-component systems that sense magnesium, iron, zinc, cationic antimicrobial peptides, and pH [765] (Table 2).
Zhang et al. [766] observed that tssC1, which is implicated in type VI secretion (T6S), is upregulated in Pseudomonas aeruginosa biofilms. The upregulation of tssC1 was important for the induction of biofilm-associated antibiotic resistance to tobramycin, gentamicin, and ciprofloxacin [766].
Dale et al. [767] studied genetic determinants that are responsible for biofilm-associated antibiotic resistance in Enterococcus faecalis and observed a role for components of the quorum-sensing system (fsrA, fsrC), the virulence-associated protease gelE, and two glycosyltransferase (GTF) genes (epaI, epaOX). FsrC is a QS histidine kinase that phosphorylates the response regulator FsrA, resulting in the expression of gelE [582]. The polysaccharide production by EpaI and EpaOX is thought to make the biofilm less penetrable for antibiotics [767].
Acinetobacter baumannii biofilms often show high antibiotic resistance [768,769]. Proteomic analysis of the biofilm-embedded Acinetobacter baumannii in comparison to those in the planktonic state showed, among others, upregulation of a membrane Fe transport protein, a sensor histidine/response regulator, diguanylate cyclase, and bacterial antibiotic resistance-related proteins such as β-lactamase PER-1 and aminoglycoside acetyltransferase type I [770].
4.7.6. Increased Efflux Pump Expression in Biofilm-Embedded Bacteria
Another reason for biofilm-associated drug resistance is the increased expression of various efflux pumps in biofilm-associated bacteria [734,771,772]. Bacteria in biofilms show higher horizontal gene transmission than planktonic bacteria [773]. The gene transfer of antibiotic-resistant genes from resistant to susceptible bacterial species within the biofilms leads to antibiotic resistance.
In Escherichia coli biofilm, RapA was found to cause antibiotic resistance to β-lactams, norfloxacin, chloramphenicol, and gentamicin through upregulating the yhcQ multidrug resistance pump [734]. A rapA mutant formed biofilms with reduced content of polysaccharides [734]. These biofilms showed better penetration of antibiotics which may explain the increased sensitivity to antibiotics [734].
The expression of RND efflux pumps and genes involved in type III secretion were upregulated in antibiotic-resistant biofilms of Pseudomonas aeruginosa that have developed in the presence of azithromycin [771]. The MexAB-OprM and MexCD-OprJ efflux pumps, but not the type III secretion system, appeared to be integral to biofilm formation in the presence of azithromycin [771].
The PA1874-1877 cluster of genes in Pseudomonas aeruginosa encodes for an efflux pump of the ATP-binding cassette (ABC) transporter complex family that is involved in the biofilm-specific antibiotic resistance [772]. Deletion of the genes encoding this pump, resulted in an increase in sensitivity to tobramycin, gentamicin, and ciprofloxacin, especially when the mutant strain was growing in a biofilm [772]. This efflux pump is expressed at a higher level in biofilm cells in comparison to planktonic cells [772].
4.8. The Relationship between Biofilm Formation and Efflux Pumps
There are several lines of evidence that efflux pumps can affect biofilm formation and contribute to bacterial colonization and persistence [151,152,719,728,774,775,776]. Efflux pumps can affect biofilm formation directly by mediating the efflux of molecules required for biofilm formation (e.g., EPS) and biofilm-regulatory QS molecules, and indirectly by regulation of transcription factors involved in biofilm formation and bacterial adhesin expression [775].
Efflux pumps are frequently upregulated in biofilms [153,734,771,772,777,778], and deletion of efflux pumps might impair biofilm formation [153,155,158,779,780]. The expression of the norB, norC, and mdeA efflux pump genes were upregulated in Staphylococcus aureus during biofilm growth [777]. Deletion of acrB and tolC in Salmonella Typhimurium impaired avian gut colonization [780]. Impaired biofilm formation was observed in Escherichia coli upon deletion of acrB, acrD, acrE, emrD, emrE, emrK, or mdtE [153,158]. The reduced biofilm formation of an AcrAB-TolC defective Salmonella Typhimurium strain was related to the repression of curli biosynthesis [774].
The MexAB-OprM efflux pump of Pseudomonas aeruginosa was shown to play an important role in biofilm formation [779]. A ΔmexAB-oprM deletion strain was compromised in its capacity to invade and transmigrate across a monolayer of Madin–Darby canine kidney (MDCK) epithelial cells and could not kill mice, in contrast to wild-type bacteria which were highly invasive and caused fatal infection [779]. The defect in the ΔmexAB-oprM strain could be complemented by the addition of culture supernatant from MDCK cells infected with wild-type bacteria, suggesting that the efflux pump exports virulence determinants that contribute to bacterial virulence [779]. Another study showed that the MexAB-OprM efflux pump is involved in the secretion of AHL autoinducers [322]. Similarly, the AdeFGH and AcrAB efflux pumps of Acinetobacter baumannii have been shown to affect biofilm and pellicle formation [781,782].
A positive correlation has been observed between the expression of the AcrAB efflux pump in drug-resistant Klebsiella pneumoniae clinical isolates and biofilm formation [719]. Other studies have found a positive correlation between the AcrAB efflux channel and Klebsiella pneumoniae virulence [783,784]. The EefABXC efflux pump of Klebsiella pneumoniae contributes to the colonization of the bacteria in the digestive tract [785]. In addition to contributing to antibiotic resistance, this efflux pump confers acid tolerance to inorganic acids [785]. The eef promoter can be induced by an acidic environment and by hyperosmolarity [785]. An AcrB knockout strain of Klebsiella pneumoniae showed a reduced capacity to cause pneumonia in a murine model [783].
Studies using efflux pump inhibitors (EPIs) showed that these compounds not only sensitize bacteria to antibiotics but also impact biofilm formation [153,154,774,786,787]. The EPIs thioridazine and Phe-Arg-βNaphtylamide (PAβN) reduced biofilm formation in Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus [153]. The MexAB-OprM-specific EPI D13-9001 reduced the invasiveness of Pseudomonas aeruginosa [788]. These findings support a role for efflux pumps in biofilm formation. Alternatively, it could be that the EPIs affect a common nodule of both processes. For instance, the endocannabinoid anandamide inhibits both drug efflux and biofilm formation of antibiotic-sensitive and antibiotic-resistant Staphylococcus aureus species [789]. Anandamide induces immediate membrane depolarization [789], an effect that has implications on both drug export and biofilm formation.
5. Targeting Quorum Sensing and Biofilms as a Strategy to Overcome Antibiotic Resistance
The multiple resistance mechanisms that have evolved in the bacteria to protect them from commonly used antibiotics have urged the need for alternative treatment therapies and the development of drugs that act on new scaffolds of targets, with the hope that these approaches could hit the Achilles’ heel of the microorganisms. These drugs can be used as a single agent or in combination with other drugs including antibiotics. The multi-purposing drug therapy aims to target different nodal points, that together will eliminate the bacteria prior to the development of resistance mechanisms. For instance, the β-lactamase inhibitor tazobactam enhanced the synergy between the β-lactam antibiotic piperacillin and daptomycin [790].
Several strategies have been developed to overcome drug resistance. These include (i) use of multiple antibiotics to overcome drug resistance [791]. This approach has the advantages of targeting multiple targets in the same bacteria, increasing drug potency by synergistic effects, and suppressing resistance evolution. (ii) Use of drugs that target the resistance mechanism(s), thus sensitizing the bacteria to the respective antibiotics [791,792]. (iii) Use of drugs that target QS [10,531,793,794]. This approach aims to reduce bacterial virulence, diminish biofilm formation, and increase the susceptibility of the bacteria to antibiotics and human defense mechanisms. (iv) Use of drugs with anti-biofilm properties [795]. These drugs should preferentially also disrupt preformed biofilms. The release of bacteria from the biofilms will make them prone to both antibiotics and human immune defense mechanisms. (v) Use of drugs that target essential cell division mechanisms such as the Z-ring division protein FtsZ, which will increase the susceptibility to antibiotics [796]. (vi) Use of drugs that target cell wall teichoic acid that will interfere with biofilm formation and increase the response to antibiotics [797,798].
Anti-virulence agents represent a promising alternative to the use of antibiotics, as these compounds suppress the production of factors involved in bacterial pathogenicity, without affecting their replication. Thus, it is less likely that therapy resistance might occur. When reducing the ability of the pathogens to colonize and invade host tissue, the drugs will enable the host immune defense mechanisms to eradicate the infection [799].
5.1. Antibiotic Adjuvants
Drugs that can sensitize resistant bacteria to antibiotics are termed antibiotic adjuvants [800]. An adjuvant is a compound that usually does not exert an antimicrobial activity by itself but can potentiate the antibiotic activity. Such adjuvants include antibiotic resistance enzyme inhibitors, efflux pump inhibitors, membrane permeabilizers, compounds leading to outer membrane disruption or inner membrane depolarization, anti-virulence compounds, QS, and biofilm inhibitors [10,531,791,792,793,794,800,801,802]. Classical examples of inhibitors of enzymes that cause antibiotic resistance are the FDA-approved β-lactamase inhibitors clavulanic acid, sulbactam, tazobactam, avibactam, and vaborbactam, which sensitize β-lactamase-expressing bacteria to penicillin antibiotics such as amoxicillin [792]. Membrane permeabilizers include polymyxin B, colistin, cationic antimicrobial peptides, glycine peptides, and caragenins [792]. The non-psychotropic phytocannabinoid cannabidiol (CBD) was found to be highly potent against Gram-positive bacteria through disruption of the bacterial membrane [803,804,805]. Interestingly, the combined treatment of CBD with polymyxin B showed a synergistic effect against some Gram-negative bacteria including Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli [804,806,807].
Repurposing Clinically Approved Drugs as Antibiotic Adjuvants
Many efforts have been invested in finding clinically approved drugs that can function as antibiotic adjuvants. The advantage of this approach is the well-established knowledge of the pharmacokinetics and toxicology of these compounds [808]. Ejim et al. [809] screened a collection of 1057 FDA-approved drugs to identify compounds that could augment the activity of the antibiotic minocycline. Among these, 69 non-antibiotic compounds including anti-inflammatory, anti-histamine, anti-spasmodic, psychotropic, and anti-hypertensive drugs, exhibited synergy with minocycline against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa [809]. Among them, the acetaldehyde dehydrogenase inhibitor disulfiram synergized with minocycline to inhibit the growth of Staphylococcus aureus. Additionally, the DOPA decarboxylase inhibitor benserazide used for Parkinson’s disease, the serotonin 5-HT receptor antagonist tegaserod used for irritable bowel disease, and the opoid receptor agonist loperamide (Imodium) used to treat diarrhea were found to sensitize Pseudomonas aeruginosa to minocycline [809]. Of note, minocycline has been found to act as an inhibitor of the AcrAB-TolC efflux pump expressed in Enterobacter species [810].
Other studies have shown that the antiretroviral zidovudine in combination with carbapenems had a synergistic activity against New Delhi Metallo-β-lactamase (NDM-1) Enterobacteriaceae strains [811] and the anti-helminthic niclosamine had anti-biofilm and antibacterial activities against Staphylococcus aureus [812,813]. Niclosamine has also been shown to have a synergistic effect with colistin on colistin-resistant Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter cloacae [814,815]. Similarly, the related anti-helminthic drug oxyclozanide could restore colistin sensitivity in drug-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae [816,817].
5.2. Quorum Sensing Inhibitors and Quenchers
Due to the tight regulation of biofilm and antibiotic resistance by the QS system, efforts have been made to find QS inhibitors or quenchers that can overcome antibiotic resistance and combat biofilm formation [5,7,8,9,10,11,12,818,819,820,821] (Table 4). QS inhibitors interfere with the action of one or more of the components of the QS system, thereby reducing the virulence and biofilm formation of the bacteria with consequently increased sensitivity to antibiotics. The concept quorum quenchers are often used for enzymes that promote the degradation of the autoinducers, thereby interrupting the QS cascade at the autoinducer receptor interaction. Histidine kinase inhibitors that target TCSs are attractive since these systems are unique to bacteria [822]. Additionally, the catalytic ATP domain of the kinases is highly conserved among the different TCSs and across bacterial species, thereby broadening the spectrum of responsive bacteria [822].
The idea of using QS inhibitors in treating biofilm-associated infections came from the observation that certain sea-weed plants (e.g., the Australian macroalga Delisea pulchra) never become covered with bacteria, which was found to be due to the production of halogenated furanones which have QS inhibition activities [925,926].
Many secondary plant metabolites have been shown to have anti-quorum and anti-biofilm activity, which may increase the sensitivity of bacteria to antibiotics [509,927,928]. These compounds are part of the plant defense system to avoid microbial infections. These metabolites usually do not have a direct antibacterial activity, but through targeting biofilm formation and QS, they are involved in protecting the plants from infective diseases through mechanisms that act in synergy with antimicrobials [927]. Halogenated thiophenones are examples of QS inhibitors that can control biofilm formation [875]. Baicalin hydrate and cinnamaldehyde target the acyl-homoserine lactone-based QS system present in Pseudomonas aeruginosa [531], and hamamelitannin targets the peptide-based system of Staphylococcus aureus [531]. Baicalin increased the susceptibility of Pseudomonas aeruginosa to tobramycin [531].
Inhibition of the alkyl-quinolone (AQ)-responding PqsR QS component of Pseudomonas aeruginosa has been attractive since PqsR activates the pqsABCDE operon encoding the autoinducer enzymes PqsABCD and PqsE, which regulates the expression of the cytotoxic galactophilic lectin protein LecA [361,929,930,931] involved in biofilm development [592], and the PhzA1 enzyme involved in the biosynthesis of the virulence factor pyocyanin [743]. Ilangovan et al. [351] developed 2-alkyl-4(3H)-quinazolinone analogs with C7 or C9 alkyl side chains (e.g., 3-NH2-7Cl-C9-QZN) that bind to PqsR and antagonize the PqsR-mediated QS signaling cascade. These inhibitors were found to inhibit Pseudomonas aeruginosa virulence at microMolar concentrations [351].
Another approach to attenuate the QS signaling and Pseudomonas aeruginosa virulence is to use enzymes (e.g., the Hod 2,4-dioxygenase) that inactivate PQS [932]. Treating Pseudomonas aeruginosa with the Hod enzyme reduced the expression of pqsA and the virulence determinants lectin A, pyocyanin, and rhamnolipids [932]. However, the proteolytic cleavage of Hod by extracellular proteases together with the competitive inhibition by the PQS precursor 2-heptyl-4(1H)-quinolone reduced the efficiency of Hod as a QS quenching agent [932].
Researchers have also developed methylated or halogenated derivates of the QS precursor anthranilate (e.g., methyl anthranilate and 2-amino-4-chlorobenzoic acid) which inhibit PQS biosynthesis probably by competing with anthranilate for the active site of the PqsA enzyme [882,933]. Methyl anthranilate inhibited the production of PQS and reduced elastase production [882]. However, high concentrations (milliMolars) are required for therapeutic effect [882]. 2-amino-4-chlorobenzoic acid and 2-amino-6-fluorobenzoic acid inhibited HAQ biosynthesis, disrupted PqsR (MvfR)-dependent gene expression, and inhibited osmoprotection [933]. Small molecule inhibitors of PqsD have also been developed [934]. PqsD is a key enzyme in the biosynthesis of 2-heptyl-4-hydroxyquinoline (HHQ) and PQS. The use of the PqsD inhibitor (2-nitrophenyl)(phenyl)-methanol reduced biofilm formation by Pseudomonas aeruginosa [934]. Grossman et al. [896] have synthesized a new series of thiazole-containing quinazolinones (e.g., 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one) capable of binding to PqsR and inhibiting the production of pyocyanin.
In a Pseudomonas aeruginosa infection model in Caenorhabditis elegans, the lignans Sesamin and Sesamolin isolated from the Sesamum indicum (L.) plant were found to prevent the infection of pre-infected worms through attenuation of QS-regulated virulence factors of the bacteria [818]. Both the lignans exerted anti-QS activity at 75 μg/mL without affecting the bacterial growth. Sesamin and Sesamolin decreased the production of virulence factors such as pyocyanin, proteases, elastase, and chitinase [818]. Additionally, the biofilm constituents of Pseudomonas aeruginosa including alginate, exopolysaccharides, and rhamnolipids were affected by the lignans [818]. The lignans acted on the LasR QS system, with minimum effect on the Rhl system [818].
Tryptophan-containing peptides with antibacterial activities impaired QS and biofilm development in multidrug-resistant Pseudomonas aeruginosa and increased the susceptibility to ceftazidime and piperacillin [820]. The tryptophan-containing peptides reduced the production of QS-regulated virulence factors by downregulating the gene expression of both the Las and Rhl QS systems [820]. Biofilm formation was inhibited by the tryptophan-containing peptides that were associated with extracellular polysaccharide production inhibition by downregulating pelA, algD, and pslA transcription [820]. In addition, the peptides reduced the expression of the efflux pump genes oprM, mexX, and mexA [820].
Garlic extracts have been shown to block QS in Pseudomonas aeruginosa [935] and sensitize the biofilm-embedded bacteria to tobramycin [936]. The garlic extract also provoked a higher degree of inflammation and improved the clearance of the bacteria in an infection model in mice [936]. Olive (Olea europaea) leaf extract reduced the expression of lasI, lasR, rhlI, and rhlR, with concomitant suppression of virulence and biofilm formation by Pseudomonas aeruginosa [937]. Additionally, ginseng (Panax ginseng) extract was found to have anti-infective activity against Pseudomonas aeruginosa by inhibiting QS [938]. The ginseng extract did not affect bacterial viability and even enhanced the extracellular protein and alginate production [938]. However, it suppressed the production of LasA and LasB and downregulated the synthesis of the AHL molecules [938]. The anti-inflammatory agent itaconic acid (methylenesuccinic acid), which is a metabolite induced during the activation of immune cells [939], increased the anti-biofilm activity of tobramycin on Pseudomonas aeruginosa, likely by facilitating the transport of tobramycin through the biofilm [940].
5.3. Inhibition of Biofilm Formation
Inhibition of biofilm formation and eradication of established biofilms are major goals to overcome antibiotic resistance and infectious diseases [795,941]. In the previous section, we discussed the inhibition of biofilm formation and sensitization to antibiotics by using QS inhibitors or QS quenchers. However, there are also compounds that prevent biofilm formation whose action mechanisms do not involve the QS system (Table 5). They may act by preventing the production of EPS, adhesion molecules, or pili formation. Efflux pump inhibitors, which will be discussed in Section 5.4, might affect biofilm formation through simultaneous inhibition of other membrane transport systems. Compounds affecting the biosynthesis of cell wall teichoic acid and lipoteichoic acid will be discussed in Section 5.5. Another approach is the inhibition of the transpeptidase Sortase A (SrtA), which is involved in the covalent attachment of adhesive matrix molecules to the peptidoglycan cell wall in Gram-positive bacteria [942], resulting in the inhibition of biofilm formation [858,943,944,945,946,947,948,949].
5.4. Inhibition of Efflux Pumps
Another approach to restore the antibacterial activity of antibiotics is to use efflux pump inhibitors (EPIs) that increase the intracellular level of the drugs [162,801,991,992,993,994] (Table 6). Different mechanisms are involved in this activity. Some efflux pump inhibitors (e.g., IITR08027 and anandamide) dispatch the protein gradient required for efflux pump activities [789,995], while others (Phe-Arg-β-naphthylamide (PAβN), phenothiazines, and 1-(1-naphthylmethyl)-piperazine) bind to an efflux pump component such as AcrB [810,996]. Many of the efflux pump inhibitors also prevent biofilm formation as discussed in Section 4.8. Many of the efflux inhibitors have not been approved for clinical uses due to their cytotoxicity, which is seemingly caused by the simultaneous targeting of various membrane-spanning transporters in humans and the need for relatively high doses to achieve the effect [792]. For instance, reserpine causes neurotoxicity via the inhibition of the mammalian ABC-system P-glycoprotein [792]. MP-601205 is an EPI that has been used in clinical trials. It was delivered as an aerosol in patients with ventilation-associated pneumonia or respiratory infections in patients with cystic fibrosis [997]. However, due to tolerability issues, these trials were discontinued [998].
Thiazolidinedione derivatives that target NorA in Staphylococcus aureus and sensitize the bacteria to fluoroquinolones [1034] have also been shown to prevent biofilm formation in mixed Streptococcus mutans-Candida albicans cultures and Candida albicans monocultures [982,1035]. Additionally, these compounds exert anti-QS activity against Vibrio harveyi by decreasing the DNA-binding activity of LuxR [984]. Additionally, these compounds exerted anti-QS activities against Pseudomonas aeruginosa by targeting the LasI quorum-sensing signal synthase [981] and PhsZ, a key enzyme in the biosynthesis of the virulent factor pyocyanin [1036].
The antipsychotic phenothiazine drug chlorpromazine has been shown to potentiate the activities of many antibiotics at subinhibitory concentrations including nalidixic acid, norfloxacin, ciprofloxacin, chloramphenicol, tetracycline, rifampicin, and streptomycin [1019,1040]. Prochlorperazine and trans(E)-flupentixol prevent drug efflux in Staphylococcus aureus species by reducing the proton motive force with a concomitant reduction in the transmembrane potential [1041]. Chlorpromazine and amitriptyline were found to be substrates and inhibitors of the AcrB multidrug efflux pump of Salmonella typhimurium and Escherichia coli [996]. Some clinically approved antimicrobial drugs have been shown to inhibit efflux pumps, including ketoconazole and minocycline [787,810]. Additionally, raloxifene used for treating osteoporosis and pyrvinium used as an anthelmintics were shown to inhibit the NorA efflux pump of Staphylococcus aureus and sensitize the bacteria to ciprofloxacin [1024]. The antidiabetic drug metformin prevents drug efflux in Staphylococcus aureus and increases their susceptibility to various antibiotics [1015]. These drugs are potential antibiotic adjuvants for the treatment of drug-resistant bacteria.
5.5. Targeting Cell Wall Teichoic Acid Synthesis
There are several lines of evidence that the presence of wall teichoic acid (WTA) in the Gram-positive Staphylococcus aureus contributes to β-lactam resistance [798,1042,1043,1044]. Moreover, WTA has been shown to protect Staphylococcus aureus against the cytotoxic effects of some unsaturated fatty acids [921,1045]. WTA plays an important role in bacterial cell wall processes and integrity and is required for proper cell division, biofilm formation, host colonization, and endovascular infection [1043,1046,1047,1048,1049]. WTA acts as a scaffold for PBP2a and is required for the proper localization of PBP4, thereby contributing to β-lactam resistance [1042]. WTA is also involved in keeping the autolysins/cell wall amidases Sle1, Atl, and LytN in the cross-wall region of the cell wall during cell division of Staphylococcus aureus [1050,1051,1052,1053]. Since Sle1 confers β-lactam resistance and promotes biofilm formation in MRSA [1054,1055], WTA may indirectly contribute to β-lactam resistance and biofilm formation via its action on the autolysin.
WTA are anionic polymers composed of repeating units of N-acetylglucosaminyl-ribitol phosphate that are modified by D-alanylation, α-O-GlcNAcylation, and β-O-GlcNAcylation [1056]. WTA are synthesized on a bactoprenol lipid carrier inside the bacterial cell before being transported to the cell surface where they are covalently linked to proteoglycans [1049,1057]. Deletion of tarO, which catalyzes the first step of WTA synthesis, or deletion of tarS, which attaches β-O-GlcNAc (β-O-N-acetyl-D-glucosamine) residues to WTA, sensitized MRSA to β-lactam antibiotics [798,1042]. Deletion of the 2-epimerase mnaA, which interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA, caused complete loss of WTA synthesis and β-lactam hypersensitivity in MRSA and methicillin-resistant Staphylococcus epidermidis [1058]. Furthermore, alanine-modified teichoic acids contribute to antimicrobial peptide resistance [1059]. The four proteins DltA-D are essential for the incorporation of D-alanine residues into WTA [1059]. Genetic inactivation of the Dlt system or chemical inhibition (D-alanylacyl-sulfamoyl-adenosine) of D-alanylation of teichoic acid sensitized MRSA to the β-lactams oxacillin and imiprenem [1060] and the cationic antimicrobial peptides nisin and gallidermin [1061]. Upregulation of the dlt operon in a Staphylococcus aureus pitA6 mutant led to daptomycin tolerance [1062].
Several compounds have been tested for their ability to interfere with WTA synthesis and the consequences on antibiotic susceptibility (Table 7). Blocking the synthesis of WTA by inhibiting the first enzyme of the pathway, TarO, by tunicamycin, sensitized MRSA to β-lactams, even in the presence of PBP2a [1043]. The blockage of WTA synthesis led to defects in septation and cell separation [1043]. Ticlopidine, which targets the N-acetylglucosamine-1-phosphate transferase encoded by tarO, increased the sensitivity of MRSA to cefuroxime [798].
The small molecule 1835F03, which inhibits WTA biosynthesis by targeting the TarGH ABC transporter involved in the translocation of WTA across the cell membrane, showed potent antibacterial activity towards several Staphylococcus aureus stains including the Newman MRSA strain [1063]. On the basis of this compound, the TarG inhibitor targocil was developed [1044,1063,1064]. Targocil treatment inhibited bacterial growth, induced osmotic stress with subsequent swelling of the cells, and downregulated the expression of numerous virulence factors [1065]. Targocil was also found to block the translocation of the major autolysin Atl across the membrane, resulting in a significant decrease in autolysis [1053]. Compounds targeting TarG could increase the susceptibility of MRSA to β-lactams such as imipenem and oxacillin [1044]. Subinhibitory concentrations of beta-lactam antibiotics could suppress the development of targocil-resistant mutants [1043].
Table 7Examples of compounds targeting wall teichoic acid (WTA) synthesis.
| Compound | Effects on Bacteria | References |
|---|---|---|
| Clomiphene |
|
[1066] |
| HSGN-94 and HSGN-189 |
|
[1067] |
| Targocil |
|
[1065] |
| Tarocin A and Tarocin B |
|
[1068] |
| Ticlopidine |
|
[798] |
| Tunicamycin |
|
[1043,1058,1069] |
5.6. Inactivation of PBP2a as an Approach to Sensitize MRSA to β-Lactams
The penicillin-binding proteins (PBPs) catalyze in separate domains the transglycosylase and transpeptidase activities involved in the biosynthesis of the cell wall peptidoglycans. β-lactam antibiotics inactivate the transpeptidase activity through irreversible acylation of an active site serine [62]. The PBP2a variant shows low affinity to β-lactams, and therefore continues to catalyze the DD-transpeptidation reaction necessary to complete the cell wall in the presence of these antibiotics [62,1070]. Since PBP2a lacks transglycosylase activity, intact cell wall synthesis requires the presence of the regular PBP2 [62,1070]. β-Lactam resistance is also achieved by elevated expression of PBP4 [1071] and the cell-division proteins FtsA, FtsW, and FtsZ [1072]. FtsZ is required for the proper localization of PBP2 to the division site where it mediates localized peptidoglycan synthesis prior to daughter cell separation [1073].
Otero et al. [1074] identified an allosteric binding domain 60 Å from the DD-transpeptidase active site of PBP2a. The binding of the β-lactam ceftaroline to the allosteric binding domain stimulated the allosteric opening of the active site, enabling a second β-lactam molecule to inactivate the PBP2a [1074]. The ability of compounds to inactivate PBP2a by allostery and thus sensitize the bacteria to antibiotics makes this protein the Achilles’ heel of MRSA [1075].
García-Fernández et al. [1076] observed that the scaffold protein flotillin facilitates oligomerization of PBP2a in functional membrane microdomains (FMMs) and drugs such as the cholesterol-lowering statin zaragozic acid, that disrupt the FMMs, prevent PBP2a oligomerization and sensitize MRSA to β-lactam antibiotics such as methicillin, oxacillin, flucoxacillin, nafcillin, and dicloxacillin. This finding can explain the observed beneficial clinical effects of statins in microbial infections [1077,1078,1079,1080]. Thus, repurposing the cholesterol-reducing drugs of the statin family can be used for overcoming β-lactam resistance to MRSA [1076].
5.7. Targeting Cell Division Proteins to Sensitize MRSA to β-Lactams
There are several lines of evidence that targeting bacteria cell division components could sensitize drug-resistant bacteria (e.g., MRSA) to antibiotics (e.g., β-lactams) [796,1081,1082,1083]. In particular, inhibition of the FtsZ cell division protein that forms a contractile ring structure termed the Z-ring at the future division sites has attracted attention [1081,1082,1084]. FtsZ mutant MRSA strains and an MRSA strain treated with FtsZ antisense displayed attenuated virulence and increased susceptibility to β-lactam antibiotics [1072,1083].
Several compounds have been developed to target FtsZ (Table 8). The FtsZ inhibitor PC190723 increases the susceptibility of MRSA to β-lactams [1083]. The effect of FtsZ inhibition is likely due to the delocalization of both FtsZ and PBP2 [1083]. Similarly, Ferrer-González et al. [1085] observed that the FtsZ inhibitor TXA707 leads to disruption of septum formation concomitant with mislocalization of PBPs from midcell to nonproductive peripheral sites [1085]. TXA707 acts synergistically with β-lactam antibiotics with a high affinity for PBP2 [1085]. This research group further observed that in the absence of TXA707, PBP1, PBP2, PBP3, and PBP4 colocalize with FtsZ at the septum of MRSA, while PBP2a localizes to distinct foci at the cell periphery [1086]. TXA707 disrupts septum formation resulting in FtsZ relocalization away from the midcell still interacting with PBP1 and PBP3 [1086]. The interaction of FtsZ with PBP2 and PBP4 was disrupted by TXA707 [1086]. When oxacillin was combined with TXA707, both PBP2 and PBP2a localized to malformed septum-like structures, which might be one mechanism how TXA707 renders MRSA susceptible to β-lactams [1086]. The combined treatment of the TXA707 prodrug TXA709 with the third-generation cephalosporine cefdinir could cure systemic and tissue infections in mice [1087].
6. Conclusions
In this review, we have presented data showing various mechanisms involved in antibiotic resistance of various ESKAPE pathogens with a specific emphasis on the triangle interconnection between quorum sensing, biofilm formation, and antibiotic resistance. A myriad of synthetic and natural compounds has been studied for their ability to interfere with one or more of these processes with the aim to eradicate biofilm and sensitize the bacteria to antibiotics. Altogether, these studies show that it is sufficient to target one or few nodal processes to overcome antibiotic resistance. A combination of these adjunctive compounds together with conventional antibiotics might be necessary to optimize their efficacy which is expected to improve the treatment regime against drug-resistant bacterial infections.
Conceptualization, R.V.S.; writing—original draft preparation, R.V.S.; writing—review and editing, R.V.S. and D.S. All authors have read and agreed to the published version of the manuscript.
Not applicable.
The authors declare no conflict of interest.
ABC—ATP-binding cassette; AHL—N-Acyl-L-homoserine lactone; AI-1—Autoinducer 1; AI-2—Autoinducer 2; AIP—Autoinducing peptide; c-di-GMP—bis-(3′-5′)-cyclic dimeric guanosine monophosphate; ECM—Extracellular matrix; eDNA—Extracellular DNA; EPI—Efflux pump inhibitor; EPS—Extracellular polymeric substances or exopolysaccharides; L-Ara4N—4-Amino-4-deoxy-L-arabinose; LPS—Lipopolysaccharides; MATE—Multidrug and toxic compound extrusion; MFS—Major facilitator superfamily; NPET—Nascent peptide exit tunnel; OMP—Outer membrane porin; QAC—Quaternary ammonium compounds; QS—Quorum sensing; QSI—Quorum sensing inhibitor; PACE—Proteobacterial antimicrobial compound efflux; PSM—Phenol-soluble modulin; PBP—Penicillin-binding protein; pEtN—Phosphoethanolamine; PTC—Peptidyl-transferase center; RND—Resistance-nodulation-cell division; RPP—Ribosomal protection proteins; SCC—Staphylococcal chromosomal cassette; SMR—Small multidrug resistance; TCS—Two-component system.
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Enlarge this image.Figure 1. (A). Induction of vancomycin resistance in Staphylococcus aureus by vancomycin. Vancomycin activates the TCS VanRS, which induces the expression of the vanHAX operon responsible for the synthesis of the D-alanyl-D-lactate dipeptide. The D-alanyl–D-lactate dipeptide shows a 1000-fold lower affinity to vancomycin compared to the regular D-alanyl–D-alanine dipeptide, thereby conferring vancomycin resistance. (B). Examples of regulatory mechanisms involved in antibiotic resistance and biofilm formation in Staphylococcus aureus. The expressions of the efflux pumps NorA and AbcA, which confer antibiotic resistance to fluoroquinolones and β-lactams, respectively, are induced by their respective substrates norfloxacin and ampicillin. Additionally, their expression levels are influenced by the ArlRS and Agr TCSs, which both affect the global transcriptional regulator MgrA (also known as NorR). Phosphorylation of MgrA by the PknB serine/theonine kinase leads to increased transcription of norA. The ArlRS and Agr TCSs are regulated by several transcriptional factors (e.g., NorG, Rot, SarA, SarR, SarZ, SigB) as illustrated in the figure. This network of regulatory factors also affects biofilm formation, where AbcA promotes biofilm formation by exporting phenol-soluble modulins (PSMs), and the Agr QS prevents biofilm formation. The Agr QS is explained in more detail in Section 3.3.
Enlarge this image.Figure 2. Induction of antibiotic resistance in Pseudomonas aeruginosa by antibiotics, zinc ions, and low concentrations of extracellular magnesium ions. The expression of the MexXY-OprM efflux pump responsible for multidrug resistance is regulated by several factors including ribosome-targeting antibiotics and the TCSs AmgRS and ParRS. AmgRS is activated by envelope stress, and ParRS is activated by the cationic antimicrobial peptide colistin as well as zinc ions. Moreover, colistin activates other TCSs including CprRS and PmrAB. The latter TCS is also affected by the TCS PhoPQ, which is activated by low extracellular magnesium ion concentrations, and extracellular DNA which sequesters magnesium ions. Extracellular DNA is a central component of Pseudomonas aeruginosa biofilms. The TCSs ParRS, CprRS, and PmrAB induce the translation of the arnBCADTEF operon which is responsible for the L-Ara4N modification of LPS, resulting in resistance to colistin. Additionally, LPS is modified by palmitoylation through PhoPQ-mediated upregulation of pagP, and by PEtN attachments regulated by the ColRS TCS.
Enlarge this image.Figure 3. Examples of antibiotic resistance mechanisms induced by bile acids. Bile salts which are secreted into the duodenum, induce the expression of various genes in bacteria that confers antibiotic resistance. Outstanding is the upregulation of efflux pumps such as MexAB-OprM in Pseudomonas aeruginosa, AcrAB-TolC in Enterobacteriaceae and EmrB/QacA in Enterococcus faecalis that confer resistance to multiple antibiotics and antiseptics, as well as to the bile salts themselves. Additionally, the TCSs BasRS and PmrAB are induced in Escherichia coli, resulting in the upregulation of the arnBCADTEF operon responsible for the L-Ara4N modification of LPS. This modification reduces the affinity of colistin/polymyxin B to LPS, with consequent resistance to these drugs.
Enlarge this image.Figure 4. Induction of antibiotic resistance by the tryptophan metabolite indole. Indole, which is produced by various gut bacteria including Escherichia coli, induces the expression of various efflux pumps (e.g., AcdD, MdtABC, AcdE, AcrAB-TolC) through activation of TCSs (e.g., BaeSR, CpxAR) or transcriptional regulators (GadX, RamA). The activity of RamA is negatively regulated by RamR.
Enlarge this image.Figure 5. Regulation of AcrAB-TolC efflux pump expression in Gram-negative bacteria. The expression of AcrAB-TolC, which confers multidrug resistance, is regulated by several transcriptional regulators including MarA, RarA, RamA, Rob, AcrR, SidA, and SoxS. MarA, in turn, is regulated by the TCSs CpxAR and QseBC, as well as various antibiotics. MarA reduces the expression of the OmpF porin which is required for the penetration of several antibiotics into the bacteria. RarA is activated by the antibiotic ertapenem. Besides upregulating AcrAB-TolC, RarA increases the expression of the OqxAB multidrug efflux pump. Bile acids and fatty acids increase AcrAB-TolC expression through repression of the Rob transcriptional regulator. SoxS is regulated by SoxR whose activity is influenced by oxidative stress, as well as by the Pseudomonas aeruginosa-produced pyocyanin pigment. In turn, SoxS increases the expression of SodA superoxide dismutase, which is a mechanism to protect the bacteria from oxidative stress. Additionally, SoxR induces the expression of the MexHI-OpmD efflux pump, thus conferring resistance to additional compounds.
Enlarge this image.Figure 6. Regulation of MexAB-OprM multidrug efflux pump expression in Pseudomonas aeruginosa. The expression of the MexAB-OprM efflux pump is positively and negatively regulated by a whole range of transcriptional regulators. Its expression is also affected by bile salts and induced by the AmgRS TCS and CpxR, which is the cognate response regulator of the CpxAR TCS.
Enlarge this image.Figure 7. Regulation of the antiholin LrgA–holin CidA system by the small SprX RNA. SprX inhibits the expression of the RNA-binding protein SpoVG, which positively regulates the TCS LytSR. LytSR positively regulates the antiholin LrgA which antagonizes the activity of the holin CidA. SpoVG induces methicillin and oxacillin resistance by promoting cell wall synthesis and inhibiting cell wall degradation. LrgA and CidA affect the response to penicillin by respectively inhibiting or activating murein hydrolase activities. Altogether, the overexpression of SprX results in increased susceptibility to β-lactams.
Enlarge this image.Figure 8. Crosstalk of the four QS systems Las, Rhl, Pqs, and Iqs in Pseudomonas aeruginosa and their relationship to biofilm formation. Each of the four TCS systems produces its own autoinducer (C12-HSL, PQS, IqsR, or C4-HSL) that acts on the corresponding receptor (LasR, PqsR, IqsR, or RhlR). The receptors, in turn, elicit phosphorelay cascades resulting in altered expression of a large number of genes. In addition, there is crosstalk between these TCSs. LasR affects PqsR, IqsR, and RhlR. There is also mutual communication between PqsR and RhlR. LasR is involved in biofilm development and maturation. PqsR is involved in early biofilm formation and the release of extracellular DNA. RhlR is involved in the maintenance of biofilm channels and the detachment of biofilm-embedded cells. IqsR promotes biofilm formation by acting on PqsR and RhlR.
Enlarge this image.Figure 9. The Agr QS system of Staphylococcus aureus. The arg operon consists of the 4 genes: agrB, agrD, agrC, and agrA. AgrD encodes for a precursor of the autoinducer peptide AIP that is processed and transported through the cell membrane by AgrB. The mature AIP interacts with its receptor AgrC eliciting a phosphorelay, resulting in the phosphorylation and activation of the response regulator AgrA that affects the expression of multiple genes including the genes of the agr operon by binding to the P2 promoter, and the RNAIII regulatory RNA by binding to the P3 promoter. RNAIII affects the expression of a large number of genes, thereby promoting the virulence of Staphylococcus aureus. A small part of the RNAIII transcript encodes for the δ-toxin (delta-hemolysin; hld). Additionally, AgrA activates the TCSs ArlRS and SaePQRS, as well as upregulating the expression of the virulence factors phenol-soluble modulins (PSMs) alpha and beta. As shown in Figure 1B, ArlRS modulates the expression of the NorA efflux channel responsible for fluoroquinolone resistance and regulates virulence factors through the induction of MgrA. The SaePQRS TCS regulates the expression of various virulence factors.
Enlarge this image.Figure 10. The Cpx envelope stress-response system. The CpxAR TCS is activated by various stress stimuli including protein misfolding, certain antibiotics, inner membrane disruption, alkaline pH, starvation, high osmolarity, and adherence to an abiotic surface. The activation of CpxAR leads to large alterations in gene expression in an attempt to protect the bacteria from the environmental stressor. Among others, it induces the expression of genes assisting in removing misfolded proteins and genes involved in biofilm formation. Additionally, CpxAR increases the expression of various genes (e.g., efflux pumps, porins, amidases, and the ldtD transpeptidase) that confer multidrug resistance and copper tolerance.
Enlarge this image.Figure 11. The role of c-di-GMP in biofilm formation and antibiotic resistance. The secondary metabolite c-di-GMP is a central mediator of biofilm formation in Gram-negative bacteria. It modulates the expression of various genes (e.g., fimX, alg44, pelD, fleQ) involved in the production of pili, flagella, alginate, and exopolysaccharides (Pel and Psl) that contribute to the development of the biofilm. Moreover, it induces the transcriptional responser BrlR that regulates the expression of efflux pumps involved in antibiotic resistance. The activity of BrlR is affected by SagS, which is involved in the molecular switch from a planktonic to a biofilm lifestyle (see Figure 12 below). The c-di-GMP level is affected by various factors including cell adhesion and cell envelope stress. Its synthesis is mediated by diguanylate cyclases (DGCs) and degraded by c-di-GMP phosphodiesterases (PDEs).
Enlarge this image.Figure 12. (A). Regulation of RsmY/RsmZ small RNAs by the GacSA TCS and c-di-GMP in Pseudomonas aeruginosa and the impact on biofilm formation. RsmY and RsmZ are small regulatory RNAs involved in the regulation of biofilm formation. Their expression is regulated by the TCS GacSA, whose activity is, in turn, regulated by the LadS, RetS, and P1611 kinases. RsmY and RsmZ sequester the translational repressor RsmA, thereby relieving its inhibitory action on c-di-GMP production and biofilm formation. Since RsmA increases motility through the type III secretion system (T3SS), an increase in the RsmY and RsmZ levels would result in reduced motility. (B). Additional TCS components regulating biofilm formation. In the planktonic state, SagS is phosphorylated and prevents the activity of BfiSR. Dephosphorylation of SagS leads to phosphorylation of BfiSR resulting in the switch from a reversible attachment to an irreversible attachment. This is followed by phosphorylation of BfmSR, which initiates biofilm maturation, and phosphorylation of MifSR, which is required for full biofilm maturation.
Examples of two-component systems (TCSs) involved in antibiotic resistance.
| TCS Involved |
Function | Bacterial Species | References |
|---|---|---|---|
| AdeRS |
|
Acinetobacter baumannii | [ |
| AirSR (YhcSR) |
|
Staphylococcus aureus | [ |
| AmgRS |
|
Pseudomonas aeruginosa | [ |
| ApsRS |
|
Staphylococcus aureus | [ |
| ArlRS |
|
Staphylococcus aureus | [ |
| BaeSR |
|
Escherichia coli, |
[ |
| BasSR |
|
Escherichia coli | [ |
| BqsRS |
|
Pseudomonas aeruginosa | [ |
| BraRS |
|
Staphylococcus aureus | [ |
| ChtRS |
|
Enterococcus faecium | [ |
| CiaRH |
|
Streptococcus pneumoniae | [ |
| ColRS |
|
Pseudomonas aeruginosa | [ |
| CopRS |
|
Pseudomonas aeruginosa | [ |
| CprRS |
|
Pseudomonas aeruginosa | [ |
| CpxAR |
|
Escherichia coli, |
[ |
| CreBC |
|
Pseudomonas aeruginosa | [ |
| CroRS |
|
Enterococcus faecium | [ |
| CzcRS |
|
Pseudomonas aeruginosa | [ |
| EvgAS |
|
Escherichia coli | [ |
| GraRS (ApsRS) |
|
Staphylococcus aureus | [ |
| LiaFSR |
|
Enterococcus faecium, |
[ |
| LrgAB |
|
Staphylococcus aureus | [ |
| LytSR |
|
Staphylococcus aureus | [ |
| NsaRS |
|
Staphylococcus aureus | [ |
| ParRS |
|
Pseudomonas aeruginosa | [ |
| PhoBR |
|
Klebsiella pneumoniae | [ |
| PhoPQ and PmrAB |
|
Pseudomonas aeruginosa, |
[ |
| QseBC |
|
Escherichia coli | [ |
| TarRS |
|
Pseudomonas aeruginosa | [ |
| VanRS |
|
Enterococcus faecium | [ |
| VraTSR |
|
Staphylococcus aureus | [ |
| WalKR (YycFG, VicRK, MicAB) |
|
Staphylococcus aureus | [ |
Examples of QS inhibitors/QS quenchers.
| Compound | Effects on Bacteria | References |
|---|---|---|
| Ajoene |
|
[ |
| Allicin |
|
[ |
|
Baicalin (5,6,7-
|
|
[ |
| Berberine |
|
[ |
|
Betulin and
|
|
[ |
|
meta
-
|
|
[ |
|
Cajaninstilbene
|
|
[ |
|
Cannabigerol (CBG) and
|
|
[ |
| Carvacrol |
|
[ |
| Cinnamic acid |
|
[ |
| Cinnamaldehyde |
|
[ |
| Clofoctol |
|
[ |
|
Clotrimazole
|
|
[ |
| Curcumin |
|
[ |
| Domperidone |
|
[ |
| Falcarindol |
|
[ |
| Flavonoids |
|
[ |
|
4-Fluoro-
|
|
[ |
| Gingerol |
|
[ |
| Halogenated furanones |
|
[ |
|
Halogenated
|
|
[ |
| Hamamelitannin |
|
[ |
|
4-
|
|
[ |
| Luteolin |
|
[ |
| Methyl anthranilate |
|
[ |
|
2-[(Methylamino)
|
|
[ |
| MHY1383 and MHY1387 |
|
[ |
| MomL |
|
[ |
| Mosloflavone |
|
[ |
| Niclosamide |
|
[ |
| Nitrofurazone and erythromycin estolate |
|
[ |
| Oritavancin |
|
[ |
| An Oxoquinazolin derivate |
|
[ |
| Paeonol |
|
[ |
|
Palmitoyl-
|
|
[ |
| Parthenolide |
|
[ |
| Phenyl lactic acid |
|
[ |
|
N-(2-Pyrimidyl)
|
|
[ |
|
Quinazolinone
|
|
[ |
| Quercetin |
|
[ |
|
Resveratrol(3,5,4′-
|
|
[ |
| Rifampicin |
|
[ |
|
Sesamin and
|
|
[ |
| Sinefungin |
|
[ |
| Staquorsin |
|
[ |
| Tryptanthrin |
|
[ |
|
Tryptophan-containing
|
|
[ |
|
Unsaturated
|
|
[ |
| Zingerone |
|
[ |
| Walkmycin B |
|
[ |
Examples of biofilm inhibitors.
| Compound | Effects on Bacteria | References |
|---|---|---|
| Astilbin |
|
[ |
| Trans-Chalcone |
|
[ |
| Chitosan |
|
[ |
| Clemastine |
|
[ |
|
Compound 62520
|
|
[ |
| DMNP—A diterpene analog |
|
[ |
|
Epigallocatechin-
|
|
[ |
| Eugenol/carvacrol |
|
[ |
| Gallium nitrate |
|
[ |
| 5-Episinuleptolide |
|
[ |
| Flavonoids |
|
[ |
| 5-Hydroxymethylfurfural |
|
[ |
| Kaempferol |
|
[ |
| α-Mangostin |
|
[ |
| Meloxicam |
|
[ |
| ML346 |
|
[ |
| Myrtenol |
|
[ |
| Orientin |
|
[ |
|
1,2,4-
|
|
[ |
| Pyrimidinedione |
|
[ |
| Pyrogallol |
|
[ |
|
Quercetin and
|
|
[ |
| Taxifolin |
|
[ |
| Thiazolidinediones (e.g., ciglitazone, TZD-C8, and thiazolidinedione-8) |
|
[ |
|
Ursolic acid
|
|
[ |
|
Virstatin (4-
|
|
[ |
| Zerumbone |
|
[ |
Examples of efflux pump inhibitors (EPIs) 1.
| Compound | Effects on Bacteria | References |
|---|---|---|
| Alkylaminoquinolines |
|
[ |
|
2-(2-Aminophenyl)
|
|
[ |
|
6-(Aryl)alkoxypyridine-
|
|
[ |
| Arylpiperazines such as 1-(1-naphthylmethyl)-piperazine (NMP) |
|
[ |
| Berberine |
|
[ |
| Boeravinone B |
|
[ |
| Boronic acid |
|
[ |
| Capsaicin |
|
[ |
| Carvacrol |
|
[ |
| Conessine |
|
[ |
|
D13-9001(A 4-oxo-
|
|
[ |
| Doxorubicin |
|
[ |
| Endocannabinoids |
|
[ |
| Eugenol derivatives |
|
[ |
| IITR08027 |
|
[ |
| Isoliquiritigenin derivates (e.g., IMRG4) |
|
[ |
| Ketoconazole |
|
[ |
|
MBX2319
|
|
[ |
| Meropenem |
|
[ |
| Metformin |
|
[ |
| Minocycline |
|
[ |
|
1-(1-Naphthylmethyl)
|
|
[ |
| Nilotinib |
|
[ |
| 5-Nitro-2-(3-phenylpropoxy)pyridine |
|
[ |
| Phenylalanine arginyl β-naphthylamide (PA β N) |
|
[ |
|
Phenothiazines such as chlorpromazine,
|
|
[ |
|
4-Phenylbenzylidene
|
|
[ |
| Piperazine derivatives |
|
[ |
| Piperine analogs |
|
[ |
|
Raloxifene and
|
|
[ |
| Reserpine |
|
[ |
| Resveratrol |
|
[ |
|
Thiazolidinedione
|
|
[ |
| Thymol |
|
[ |
| Totarol |
|
[ |
| Trimethoprim |
|
[ |
| Verapamil |
|
[ |
1 In the studies claiming that the compound inhibits NorA, the research was performed on a Staphylococcus aureus strain (SA-1199B) that overexpresses NorA, but it could be that these compounds also interfere with other efflux pumps.
Examples of compounds targeting cell division components.
| Compound | Effects on Bacteria | References |
|---|---|---|
| A benzofuroquinolinium derivative |
|
[ |
| Berberine |
|
[ |
| Cinnamaldehyde |
|
[ |
| 1-Methylquinolinium iodide derivative |
|
[ |
| PC190723 |
|
[ |
| Quinuclidine 1 |
|
[ |
| TXA707 |
|
[ |
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