8E4A

Pseudomonas LpxC in complex with LPC-233

8E4A の概要

• エントリーDOI: 10.2210/pdb8e4a/pdb
• 分子名称: UDP-3-O-acyl-N-acetylglucosamine deacetylase, ZINC ION, 4-(4-cyclopropylbuta-1,3-diyn-1-yl)-N-[(2S,3S)-4,4-difluoro-3-hydroxy-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl]benzamide, ... (4 entities in total)
• 機能のキーワード: lpxc, lipid a, biosynthetic protein
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33588.38

構造登録者

Najeeb, J.,Zhou, P. (登録日: 2022-08-17, 公開日: 2023-08-23)

主引用文献

Zhao, J.,Cochrane, C.S.,Najeeb, J.,Gooden, D.,Sciandra, C.,Fan, P.,Lemaitre, N.,Newns, K.,Nicholas, R.A.,Guan, Z.,Thaden, J.T.,Fowler Jr., V.G.,Spasojevic, I.,Sebbane, F.,Toone, E.J.,Duncan, C.,Gammans, R.,Zhou, P.
Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.
Sci Transl Med, 15:eadf5668-eadf5668, 2023

PubMed Abstract: 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. 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.

PubMed: 37556556
DOI: 10.1126/scitranslmed.adf5668

実験手法

X-RAY DIFFRACTION (2.034 Å)