Nature 533, 338–345 (2016)

Macrolide antibiotics exhibit potent activity against human pathogens, but generating synthetic and engineered biosynthetic routes to new members of this class has proven difficult. All of the macrolide antibiotics currently approved for use in humans have been manufactured through semisynthesis from erythromycin, a strategy that is restricted by the limited functional groups on the molecule that can be easily modified and by the challenge of selectively modifying them. Seiple et al. report a new synthetic approach to macrolide production involving a highly convergent assembly process from simple building blocks, which allows the diversification of macrolide structures through incorporation of a wide variety of functional groups. Using this system, the authors prepared over 300 macrolide compounds from the azaketolide and ketolide subclasses, including the approved drug telithromycin and the clinical candidate solithromycin. When the compound library was tested against a panel of bacterial strains, the majority exhibited antibiotic activity, and two compounds in particular were found to be more potent than any other macrolide currently in clinical use for the treatment of antibiotic-resistant pathogens. This synthetic approach provides a potentially important new strategy for the development of new antibiotics needed to combat the advance of antibiotic resistance and a tool to optimize their properties for use in humans.