Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 114, Issue -, Pages 318-327Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.03.017
Keywords
Metallo-beta-lactamase; Enzyme inhibitor; Antibiotic resistance
Categories
Funding
- University of Queensland
- National Health and Medical Research Council (NHMRC) of Australia [APP1084778]
- Australian Research Council [FT120100694]
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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.
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