Mechanism and Inhibition of LpxC: An Essential Zinc-Dependent Deacetylase of Bacterial Lipid A Synthesis
- 1 February 2008
- journal article
- review article
- Published by Bentham Science Publishers Ltd. in Current Pharmaceutical Biotechnology
- Vol. 9 (1), 9-15
- https://doi.org/10.2174/138920108783497668
Abstract
Multi-drug resistant (MDR), pathogenic Gram-negative bacteria pose a serious health threat, and novel antibiotic targets must be identified to combat MDR infections. One promising target is the zinc-dependent metalloamidase UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC), which catalyzes the committed step of lipid A (endotoxin) biosynthesis. LpxC is an essential, single copy gene that is conserved in virtually all Gram-negative bacteria. LpxC structures, revealed by NMR and X-ray crystallography, demonstrate that LpxC adopts a novel ‘β-α-α-β sandwich’ fold and encapsulates the acyl chain of the substrate with a unique hydrophobic passage. Kinetic analysis revealed that LpxC functions by a general acid-base mechanism, with a glutamate serving as the general base. Many potent LpxC inhibitors have been identified, and most contain a hydroxamate group targeting the catalytic zinc ion. Although early LpxC-inhibitors were either narrow-spectrum antibiotics or broad-spectrum in vitro LpxC inhibitors with limited antibiotic properties, the recently discovered compound CHIR-090 is a powerful antibiotic that controls the growth of Escherichia coli and Pseudomonas aeruginosa, with an efficacy rivaling that of the FDA-approved antibiotic ciprofloxacin. CHIR-090 inhibits a wide range of LpxC enzymes with sub-nanomolar affinity in vitro, and is a two-step, slow, tight-binding inhibitor of Aquifex aeolicus and E. coli LpxC. The success of CHIR-090 suggests that potent LpxCtargeting antibiotics may be developed to control a broad range of Gram-negative bacteria.This publication has 32 references indexed in Scilit:
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