Techniques: Chemical synthesis platform to create structurally diverse libraries of macrolide antibiotics

A platform for modular synthesis of macrocyclic macrolide antibiotics could generate more chemically diverse libraries of antibacterial compounds than semisynthesis-based methods of macrolide production. The platform utilized eight small molecule building blocks and a series of chemical modifications and coupling reactions on those blocks to yield chemically diverse libraries of macrocyclic macrolides, including those based on 14- and 15-carbon azaketolide scaffolds and 14-carbon ketolide scaffolds. In proof-of-concept experiments the platform was used to synthesize over 300 novel compounds, including four that had greater potency against five Gram-negative bacterial species and five erythromycin-resistant Gram-positive bacterial strains than Ketek telithromycin or solithromycin. Next steps include developing chemical synthesis platforms for additional classes of antibiotics.

Merck & Co. Inc. has both IV and oral formulations of solithromycin, a fluoroketolide/macrolide antibiotic, in registration to treat pneumonia, and has the oral formulation in Phase III testing to treat uncomplicated Neisseria gonorrhoeae infection and Phase I testing for a variety of other bacterial infections. ...