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Article Dans Une Revue Science Translational Medicine Année : 2023

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

Jinshi Zhao
C. Skyler Cochrane
Javaria Najeeb
David Gooden
Carly Sciandra
  • Fonction : Auteur
Ping Fan
  • Fonction : Auteur
Kate Newns
Robert Nicholas
Ziqiang Guan
Joshua Thaden
Vance Fowler
Ivan Spasojevic
Florent Sebbane
  • Fonction : Auteur
Eric Toone
Clayton Duncan
  • Fonction : Auteur
Richard Gammans
Pei Zhou

Résumé

The UDP-3- O -( R -3-hydroxyacyl)- N -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.
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Dates et versions

hal-04558773 , version 1 (25-04-2024)

Identifiants

Citer

Jinshi Zhao, C. Skyler Cochrane, Javaria Najeeb, David Gooden, Carly Sciandra, et al.. Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens. Science Translational Medicine, 2023, 15 (708), ⟨10.1126/scitranslmed.adf5668⟩. ⟨hal-04558773⟩
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