Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1

Arjomandi, Omid Khalili, Hussein, Waleed M., Vella, Peter, Yusof, Yusralina, Sidjabat, Hanna E., Schenk, Gerhard and McGeary, Ross P. (2016) Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1. European Journal of Medicinal Chemistry, 114 318-327. doi:10.1016/j.ejmech.2016.03.017

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Author Arjomandi, Omid Khalili
Hussein, Waleed M.
Vella, Peter
Yusof, Yusralina
Sidjabat, Hanna E.
Schenk, Gerhard
McGeary, Ross P.
Title Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1
Formatted title
Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1
Journal name European Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0223-5234
1768-3254
Publication date 2016-03-09
Year available 2016
Sub-type Article (original research)
DOI 10.1016/j.ejmech.2016.03.017
Open Access Status File (Author Post-print)
Volume 114
Start page 318
End page 327
Total pages 10
Place of publication Issy les Moulineaux, Cedex, France
Publisher Elsevier Masson
Language eng
Subject 3004 Pharmacology
3002 Drug Discovery
1605 Organic Chemistry
Abstract There are currently no clinically available inhibitors of metallo-beta-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used beta-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of L-amino acids were designed and synthesized, and their inhibitory effects against the metallo-beta-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from L-tyrosine, exhibited competitive inhibition, with a K-i of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2-fold were observed. (C) 2016 Elsevier Masson SAS. All rights reserved.
Formatted abstract
There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2 - fold were observed.
Keyword Antibiotic Resistance
Enzyme inhibitor
Metallo-β-lactamase
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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Created: Sat, 02 Apr 2016, 00:20:32 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences