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

Ricky Cain, Jürgen Brem, David Zollman, Michael A. McDonough, Rachel M. Johnson, James Spencer, Anne Makena, Martine I. Abboud, Samuel Cahill, Sook Y. Lee, Peter J. McHugh, Christopher J. Schofield*, Colin W.G. Fishwick

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

20 Citations (Scopus)
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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 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.

Original languageEnglish
Pages (from-to)1255-1260
Number of pages6
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
Early online date22 Dec 2017
DOIs
Publication statusPublished - 8 Feb 2018

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    Cain, R., Brem, J., Zollman, D., McDonough, M. A., Johnson, R. M., Spencer, J., Makena, A., Abboud, M. I., Cahill, S., Lee, S. Y., McHugh, P. J., Schofield, C. J., & Fishwick, C. W. G. (2018). In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors. Journal of Medicinal Chemistry, 61(3), 1255-1260. https://doi.org/10.1021/acs.jmedchem.7b01728