Evaluation of a potent LpxC inhibitor for post-exposure prophylaxis treatment of antibiotic-resistant in a murine infection model.

LPC-233 (a.k.a.

Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.

The UDP-3--(-3-hydroxyacyl)--acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting antibiotics toward clinical therapeutics has been hindered by the limited antibiotic profile of reported non-hydroxamate inhibitors and unexpected cardiovascular toxicity observed in certain hydroxamate and non-hydroxamate-based inhibitors. Here, we report the preclinical characterization of a slow, tight-binding LpxC inhibitor, LPC-233, with low picomolar affinity.