In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL...

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Published inJournal of medicinal chemistry Vol. 61; no. 3; pp. 1255 - 1260
Main Authors Cain, Ricky, Brem, Jürgen, Zollman, David, McDonough, Michael A, Johnson, Rachel M, Spencer, James, Makena, Anne, Abboud, Martine I, Cahill, Samuel, Lee, Sook Y, McHugh, Peter J, Schofield, Christopher J, Fishwick, Colin W. G
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 08.02.2018
Amer Chemical Soc
Subjects
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
beta-Lactamase Inhibitors - chemistry
beta-Lactamase Inhibitors - pharmacology
beta-Lactamases - chemistry
beta-Lactamases - metabolism
Chemistry, Medicinal
Computer Simulation
Drug Design
Drug Evaluation, Preclinical
Life Sciences & Biomedicine
Models, Molecular
Pharmacology & Pharmacy
Protein Conformation
Science & Technology
Structure-Activity Relationship
LEADS
RESISTANCE
SPROUT
STRUCTURAL BASIS
CRYSTAL-STRUCTURE
DISCOVERY
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Summary:Zinc ion-dependent β-lactamases (MBLs) catalyze the hydrolysis of almost all β-lactam antibiotics and resist the action of clinically available β-lactamase inhibitors. We report how application of in silico fragment-based molecular design employing thiol-mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors manifest potent inhibition of clinically important B1 subfamily MBLs, including the widespread NDM-1, IMP-1, and VIM-2 enzymes; with lower potency, some of them also inhibit clinically relevant Class A and D serine-β-lactamases. The inhibitors show selectivity for bacterial MBL enzymes compared to that for human MBL fold nucleases. Cocrystallization of one inhibitor, which shows potentiation of Meropenem activity against MBL-expressing Enterobacteriaceae, with VIM-2 reveals an unexpected binding mode, involving interactions with residues from conserved active site bordering loops.
Bibliography:researchfish
UKRI
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01728