Cain, R, Brem, J, Zollman, D et al. (10 more authors) (2018) In silico fragment based design identifies subfamily B1 metallo-β-lactamase inhibitors. Journal of Medicinal Chemistry, 61 (3). pp. 1255-1260. ISSN 0022-2623
Abstract
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 human MBL fold nucleases. Co-crystallization 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017, American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright (c) American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see: https://doi.org/10.1021/acs.jmedchem.7b01728 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Feb 2018 15:46 |
Last Modified: | 22 Dec 2018 01:39 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.jmedchem.7b01728 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:127461 |