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The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.
Natural products have provided critical starting points for the development of a majority of the antibacterial drugs listed as essential medicines by the World Health Organization. During the period from about 1940 to 1960, sometimes described as the golden age of antibiotics research, academic and industrial laboratories identified the natural products that went on to define many of the major classes of modern antibiotics1. Few if any natural products prove to be optimal for safety, efficacy or oral use in humans, however, for these were probably not evolutionary pressures for the microbes in which they developed. For six decades a primary tool by which new antibiotics have been discovered and manufactured is semisynthesis, or the chemical modification of natural products derived from fermentation. Semisynthesis is inherently limited because it is challenging to modify structurally complex natural products selectively, and typically few positions of any given scaffold can be modified effectively2,3. Macrolide antibiotics (macrocyclic lactones with one or more pendant glycosidic residues), which have proven to be safe and effective for use in treating human infectious diseases such as community-acquired bacterial pneumonia, gonorrhoea and others, provide a compelling case in point. Since the discovery of erythromycin from a Philippine soil sample in 19494, in spite of extraordinary efforts leading to fully synthetic5-8 and modified...