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Title: Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A [beta]-Lactamase

Abstract

The emergence of CTX-M class A extended-spectrum {beta}-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K{sub i} = 21 {mu}M) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K{sub i} value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli. The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A {beta}-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.

Authors:
; ; ; ; ; ; ; ;  [1]
  1. USF
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERUNIVERSITY
OSTI Identifier:
1039775
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 55; Journal Issue: (5) ; 03, 2012; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; DESIGN; EFFICIENCY; ESCHERICHIA COLI; FUNCTIONALS; HOT SPOTS; IN VITRO; MODIFICATIONS

Citation Formats

Nichols, Derek A, Jaishankar, Priyadarshini, Larson, Wayne, Smith, Emmanuel, Liu, Guoqing, Beyrouthy, Racha, Bonnet, Richard, Renslo, Adam R, Chen, Yu, UCSF), and Clermont). Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A [beta]-Lactamase. United States: N. p., 2012. Web. doi:10.1021/jm2014138.
Nichols, Derek A, Jaishankar, Priyadarshini, Larson, Wayne, Smith, Emmanuel, Liu, Guoqing, Beyrouthy, Racha, Bonnet, Richard, Renslo, Adam R, Chen, Yu, UCSF), & Clermont). Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A [beta]-Lactamase. United States. https://doi.org/10.1021/jm2014138
Nichols, Derek A, Jaishankar, Priyadarshini, Larson, Wayne, Smith, Emmanuel, Liu, Guoqing, Beyrouthy, Racha, Bonnet, Richard, Renslo, Adam R, Chen, Yu, UCSF), and Clermont). 2012. "Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A [beta]-Lactamase". United States. https://doi.org/10.1021/jm2014138.
@article{osti_1039775,
title = {Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A [beta]-Lactamase},
author = {Nichols, Derek A and Jaishankar, Priyadarshini and Larson, Wayne and Smith, Emmanuel and Liu, Guoqing and Beyrouthy, Racha and Bonnet, Richard and Renslo, Adam R and Chen, Yu and UCSF) and Clermont)},
abstractNote = {The emergence of CTX-M class A extended-spectrum {beta}-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K{sub i} = 21 {mu}M) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K{sub i} value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli. The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A {beta}-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design.},
doi = {10.1021/jm2014138},
url = {https://www.osti.gov/biblio/1039775}, journal = {J. Med. Chem.},
issn = {0022-2623},
number = (5) ; 03, 2012,
volume = 55,
place = {United States},
year = {Wed Jul 11 00:00:00 EDT 2012},
month = {Wed Jul 11 00:00:00 EDT 2012}
}