Skip to main content
Journal cover image

Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.

Publication ,  Journal Article
Barb, AW; Leavy, TM; Robins, LI; Guan, Z; Six, DA; Zhou, P; Hangauer, MJ; Bertozzi, CR; Raetz, CRH
Published in: Biochemistry
April 14, 2009

The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A (endotoxin) biosynthesis in Gram-negative bacteria and is a validated antibiotic target. Although several previously described compounds bind to the unique acyl chain binding passage of LpxC with high affinity, strategies to target the enzyme's UDP-binding site have not been reported. Here the identification of a series of uridine-based LpxC inhibitors is presented. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of Escherichia coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Compound 1-68A exhibits a K(I) of 54 muM and a maximal rate of inactivation (k(inact)) of 1.7 min(-1) at pH 7.4. Dithiothreitol, glutathione and the C207A mutant of E. coli LpxC prevent the formation of a covalent complex by 1-68A, suggesting a role for Cys-207 in inhibition. The inhibitory activity of 1-68A and a panel of synthetic analogues identified moieties necessary for inhibition. 1-68A and a 2-dehydroxy analogue, 1-68Aa, inhibit several purified LpxC orthologues. These compounds may provide new scaffolds for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Biochemistry

DOI

EISSN

1520-4995

Publication Date

April 14, 2009

Volume

48

Issue

14

Start / End Page

3068 / 3077

Location

United States

Related Subject Headings

  • Uridine
  • Structure-Activity Relationship
  • Kinetics
  • Escherichia coli Proteins
  • Escherichia coli
  • Enzyme Inhibitors
  • Biochemistry & Molecular Biology
  • Anti-Bacterial Agents
  • Amidohydrolases
  • 3404 Medicinal and biomolecular chemistry
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Barb, A. W., Leavy, T. M., Robins, L. I., Guan, Z., Six, D. A., Zhou, P., … Raetz, C. R. H. (2009). Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry, 48(14), 3068–3077. https://doi.org/10.1021/bi900167q
Barb, Adam W., Tanya M. Leavy, Lori I. Robins, Ziqiang Guan, David A. Six, Pei Zhou, Matthew J. Hangauer, Carolyn R. Bertozzi, and Christian R. H. Raetz. “Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.Biochemistry 48, no. 14 (April 14, 2009): 3068–77. https://doi.org/10.1021/bi900167q.
Barb AW, Leavy TM, Robins LI, Guan Z, Six DA, Zhou P, et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry. 2009 Apr 14;48(14):3068–77.
Barb, Adam W., et al. “Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.Biochemistry, vol. 48, no. 14, Apr. 2009, pp. 3068–77. Pubmed, doi:10.1021/bi900167q.
Barb AW, Leavy TM, Robins LI, Guan Z, Six DA, Zhou P, Hangauer MJ, Bertozzi CR, Raetz CRH. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry. 2009 Apr 14;48(14):3068–3077.
Journal cover image

Published In

Biochemistry

DOI

EISSN

1520-4995

Publication Date

April 14, 2009

Volume

48

Issue

14

Start / End Page

3068 / 3077

Location

United States

Related Subject Headings

  • Uridine
  • Structure-Activity Relationship
  • Kinetics
  • Escherichia coli Proteins
  • Escherichia coli
  • Enzyme Inhibitors
  • Biochemistry & Molecular Biology
  • Anti-Bacterial Agents
  • Amidohydrolases
  • 3404 Medicinal and biomolecular chemistry