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Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis.

Publication ,  Journal Article
Barb, AW; Zhou, P
Published in: Curr Pharm Biotechnol
February 2008

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 'beta-alpha-alpha-beta 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 LpxC-targeting antibiotics may be developed to control a broad range of Gram-negative bacteria.

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Published In

Curr Pharm Biotechnol

DOI

EISSN

1873-4316

Publication Date

February 2008

Volume

9

Issue

1

Start / End Page

9 / 15

Location

Netherlands

Related Subject Headings

  • Zinc
  • Threonine
  • Lipid A
  • Hydroxamic Acids
  • Humans
  • Escherichia coli Proteins
  • Biotechnology
  • Animals
  • Amidohydrolases
  • 3214 Pharmacology and pharmaceutical sciences
 

Citation

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Barb, A. W., & Zhou, P. (2008). Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol, 9(1), 9–15. https://doi.org/10.2174/138920108783497668
Barb, Adam W., and Pei Zhou. “Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis.Curr Pharm Biotechnol 9, no. 1 (February 2008): 9–15. https://doi.org/10.2174/138920108783497668.
Barb, Adam W., and Pei Zhou. “Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis.Curr Pharm Biotechnol, vol. 9, no. 1, Feb. 2008, pp. 9–15. Pubmed, doi:10.2174/138920108783497668.

Published In

Curr Pharm Biotechnol

DOI

EISSN

1873-4316

Publication Date

February 2008

Volume

9

Issue

1

Start / End Page

9 / 15

Location

Netherlands

Related Subject Headings

  • Zinc
  • Threonine
  • Lipid A
  • Hydroxamic Acids
  • Humans
  • Escherichia coli Proteins
  • Biotechnology
  • Animals
  • Amidohydrolases
  • 3214 Pharmacology and pharmaceutical sciences