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Abstract
The increase of antibiotic resistance is a result of widespread overuse of antibiotics and less approval of novel therapeutics. Developing better tools for clinical diagnosis and better methods for antibiotic development will reduce the incidence of infections of current antibiotic resistant strains and prevent the emergence of new antibiotic-resistant strains. Positron emission tomography (PET), which is a quantitative form of medical imaging, is currently used for diagnosing and monitoring cancer tumors but the use of PET can be expanded by developing new tracers to monitor other diseases, such as bacterial infections. We hypothesize that PET can be used to diagnose/monitor bacterial infections and improve pharmacokinetic and pharmacodynamic (PK/PD) modeling for more efficient development of antibiotics. As a quantitative method, PET can be used to determine the amount of bacterial cells in vivo and monitor an infection over the course of antibiotic treatment. We have developed 18F-PABA, which is an alternate substrate in the tetrahydrofolate biosynthesis pathway of bacteria. As a tracer, 18 F-PABA can specifically identify S. aureus infections as low as 6 log10 CFU in vivo while clearing out of healthy organs and inflammatory cells. PET can also be used to determine the concentration of drug at the site of action, which would improve PK analysis. 18F-3C-DPE is a tracer with a structure similar to other diphenyl ether scaffold inhibitors that are known to inhibit FabI, an enoyl-ACP reductase essential to the fatty acid biosynthesis pathway. This PET tracer has been developed to better predict in vivo efficacy by quantifying in vivo PK at the infection site. The development of 18F-PABA and 18F-3C-DPE is a step towards improving antibiotic development to prevent and reduce the emergence of antibiotic-resistant bacterial infections.
