A Platform for the Discovery of New Macrolide Antibiotics

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool for 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 efficacious, as bacterial resistance to many of these compounds has developed. In this manuscript, we describe a practical, fully synthetic route to macrolide antibiotics via the convergent assembly of simple chemical building blocks, with diverse structures not possible by traditional semisynthesis. More than 300 new macrolide antibiotic candidates, as well as the investigational drug solithromycin, were synthesized by our convergent approach. Evaluation of the novel compounds against a panel of pathogenic bacteria revealed many antibiotic candidates, with efficacy against strains resistant to macrolides in current use. The chemistry we describe herein provides a platform for the discovery of new macrolide antibiotics and may also serve as a basis for their manufacture.