Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens
Jinshi Zhao, C. Skyler Cochrane, Javaria Najeeb, David M. Gooden, Carly A. Sciandra, Ping Fan, Nadine Lemaître, Kate Newns, Robert A. Nicholas, Ziqiang Guan, Joshua T. Thaden, Vance G. Fowler, Ivan Spasojević, Florent Sebbane, Eric J. Toone, Clayton Duncan, Richard E. Gammans, Pei Zhou
Abstract
-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. The compound is a rapid bactericidal antibiotic, unaffected by established resistance mechanisms to commercial antibiotics, and displays outstanding activity against a wide range of Gram-negative clinical isolates in vitro. It is orally bioavailable and efficiently eliminates infections caused by susceptible and multidrug-resistant Gram-negative bacterial pathogens in murine soft tissue, sepsis, and urinary tract infection models. It displays exceptional in vitro and in vivo safety profiles, with no detectable adverse cardiovascular toxicity in dogs at 100 milligrams per kilogram. These results establish the feasibility of developing oral LpxC-targeting antibiotics for clinical applications.