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Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics.

Publication ,  Journal Article
Cho, J; Lee, M; Cochrane, CS; Webster, CG; Fenton, BA; Zhao, J; Hong, J; Zhou, P
Published in: Proc Natl Acad Sci U S A
February 25, 2020

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an LpxH-targeting sulfonyl piperazine compound (referred to as AZ1) by AstraZeneca. However, the molecular details of AZ1 inhibition have remained unresolved, stymieing further development of this class of antibiotics. Here we report the crystal structure of Klebsiella pneumoniae LpxH in complex with AZ1. We show that AZ1 fits snugly into the L-shaped acyl chain-binding chamber of LpxH with its indoline ring situating adjacent to the active site, its sulfonyl group adopting a sharp kink, and its N-CF3-phenyl substituted piperazine group reaching out to the far side of the LpxH acyl chain-binding chamber. Intriguingly, despite the observation of a single AZ1 conformation in the crystal structure, our solution NMR investigation has revealed the presence of a second ligand conformation invisible in the crystalline state. Together, these distinct ligand conformations delineate a cryptic inhibitor envelope that expands the observed footprint of AZ1 in the LpxH-bound crystal structure and enables the design of AZ1 analogs with enhanced potency in enzymatic assays. These designed compounds display striking improvement in antibiotic activity over AZ1 against wild-type K. pneumoniae, and coadministration with outer membrane permeability enhancers profoundly sensitizes Escherichia coli to designed LpxH inhibitors. Remarkably, none of the sulfonyl piperazine compounds occupies the active site of LpxH, foretelling a straightforward path for rapid optimization of this class of antibiotics.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 25, 2020

Volume

117

Issue

8

Start / End Page

4109 / 4116

Location

United States

Related Subject Headings

  • Pyrophosphatases
  • Protein Conformation
  • Piperazines
  • Mutation
  • Microbial Sensitivity Tests
  • Lipid Metabolism
  • Klebsiella pneumoniae
  • Gene Expression Regulation, Bacterial
  • Escherichia coli
  • Bacterial Proteins
 

Citation

APA
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Cho, J., Lee, M., Cochrane, C. S., Webster, C. G., Fenton, B. A., Zhao, J., … Zhou, P. (2020). Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics. Proc Natl Acad Sci U S A, 117(8), 4109–4116. https://doi.org/10.1073/pnas.1912876117
Cho, Jae, Minhee Lee, C Skyler Cochrane, Caroline G. Webster, Benjamin A. Fenton, Jinshi Zhao, Jiyong Hong, and Pei Zhou. “Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics.Proc Natl Acad Sci U S A 117, no. 8 (February 25, 2020): 4109–16. https://doi.org/10.1073/pnas.1912876117.
Cho J, Lee M, Cochrane CS, Webster CG, Fenton BA, Zhao J, et al. Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4109–16.
Cho, Jae, et al. “Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics.Proc Natl Acad Sci U S A, vol. 117, no. 8, Feb. 2020, pp. 4109–16. Pubmed, doi:10.1073/pnas.1912876117.
Cho J, Lee M, Cochrane CS, Webster CG, Fenton BA, Zhao J, Hong J, Zhou P. Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4109–4116.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

February 25, 2020

Volume

117

Issue

8

Start / End Page

4109 / 4116

Location

United States

Related Subject Headings

  • Pyrophosphatases
  • Protein Conformation
  • Piperazines
  • Mutation
  • Microbial Sensitivity Tests
  • Lipid Metabolism
  • Klebsiella pneumoniae
  • Gene Expression Regulation, Bacterial
  • Escherichia coli
  • Bacterial Proteins