Chemoenzymatic Synthesis of Glycosylated Macrolactam Analogues of the Macrolide Antibiotic YC-17

Abstract

YC-17 is a 12-membered ring macrolide antibiotic produced from Streptomyces venezuelae ATCC 15439 and is composed of the polyketide macrolactone 10-deoxymethynolide appended with D-desosamine. In order to develop structurally diverse macrolactam analogues of YC-17 with improved therapeutic potential, a combined approach involving chemical synthesis and engineered cell-based biotransformation was employed. Eight new antibacterial macrolactam analogues of YC-17 were generated by supplying a novel chemically synthesized macrolactam aglycone to S. venezuelae mutants harboring plasmids capable of synthesizing several unnatural sugars for subsequent glycosylation. Some YC-17 macrolactam analogues were active against erythromycin-resistant bacterial pathogens and displayed improved metabolic stability in vitro. The enhanced therapeutic potential demonstrated by these glycosylated macrolactam analogues reveals the unique potential of chemoenzymatic synthesis in antibiotic drug discovery and development.