A Decade of Research on Daptomycin

Abstract Daptomycin is a calcium-dependent cyclic lipodepsipeptide antibiotic that is used in the clinic for treating serious infections caused by Gram-positive bacteria. In this account, I present a summary of the research that has been conducted in my group on daptomycin’s total chemical synthesis, its structure–activity relationships, and its mechanism of action, since we began our studies a decade ago. 1 Introduction 2 Solid-Phase Synthesis of Daptomycin by an On-Resin Cyclization 3 α-Azido Acids and Alternative Routes to Daptomycin by On-Resin Cyclization 4 Synthesis of Daptomycin by an Off-Resin Cyclization 5 SAR Studies on Daptomycin 6 Oligomerization of Daptomycin on Membranes 7 The Chiral Target of Daptomycin 8 SAR Studies on Phosphatidylglycerol 9 Conclusions