Structure‐activity relationships of diacetylene‐based LpxC inhibitors

Abstract

The LpxC enzyme in the lipid A biosynthesis pathway is one of most promising and yet clinically unexploited antibiotic targets for the treatment of multidrug‐resistant Gram‐negative infections. Unfortunately, extant LpxC inhibitors typically display large variations in potency against different Gram‐negative pathogens. Recently, structural studies in our laboratory revealed that significant structural variations exist among diverse LpxC orthologs. When LpxC orthologs bind to LPC‐009 inhibitor, the vicinity of the active site displays large conformational variations, creating different morphologies of the substrate‐binding hydrophobic passage. The LPC‐009 inhibitor whose pliable diacetylene scaffold is essential for its broad‐spectrum inhibition overcomes structural variations in the hydrophobic passages of LpxC orthologs. To further improve potency and antibiotic profiles of LPC‐009, a series of diacetylene‐based derivatives were designed from the lead compound LPC‐009, synthesized and evaluated for antibiotic profiles against diverse Gram‐negative pathogens. In addition, the crystal structures of LpxC in complex with newly designed LpxC inhibitors provide insights for structure‐activity relationships and future structure‐based optimization of LpxC inhibitors.This research was supported by National Institutes of Health Grants AI055588 (to P.Z.) and GM‐51310 (to C.RH.R).