Species-specific and Inhibitor-dependent Conformations of LpxC: Implications for Antibiotic Design

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2010 Dec 21

PMID 21167751

Citations 38

Authors

Chul-Jin Lee

Xiaofei Liang

Xin Chen

Daina Zeng

Sang Hoon Joo

Hak Suk Chung

Adam W Barb

Shauna M Swanson

Robert A Nicholas

Yaoxian Li

Eric J Toone

Christian R H Raetz

Pei Zhou

Affiliations

Soon will be listed here.

Abstract

LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.

Citing Articles

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