Model for antibiotic optimization via neoglycosylation: synthesis of liponeoglycopeptides active against VRE

Abstract

The neoglycosylation of a methoxyamine-appended vancomycin aglycon with all possible N'-decanoylglucopyranose and N'-biphenoylglucopyranose regioisomers led to the production of a focused set of liponeoglycopeptide variants in good yields and with excellent stereoselectivity. High-throughput antibacterial assays employing a unique set of vancomycin-resistant Enterococci faecalis and Enterococci faecium clinical isolates revealed that the nature and regiochemistry of glycosyl lipidation modulated vancomycin-resistent Enterococci potency. In contrast to prior work with lipoglycopeptides, this study reveals the glucose C3' or C4' as the optimal position for neoglycopeptide lipidation. This purely chemical method for the diversification of the glycolipid portion of lipoglycopeptide antibiotics is simple to perform on a large scale, requires minimal synthetic effort in sugar donor preparation, and provides access to highly active antibiotics that are not easily prepared by other state-of-the-art methods.