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

Research output: Contribution to journalArticle

  • 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
Original languageEnglish
Pages (from-to)1255-1260
Number of pages6
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
Early online date22 Dec 2017
DOIs
DateAccepted/In press - 22 Dec 2017
DateE-pub ahead of print - 22 Dec 2017
DatePublished (current) - 8 Feb 2018

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.

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via ACS at https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01728 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 687 KB, PDF document

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