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Will morphing boron-based inhibitors beat the β-lactamases?

Authors
  • Krajnc, Alen1
  • Lang, Pauline A1
  • Panduwawala, Tharindi D1
  • Brem, Jürgen1
  • Schofield, Christopher J2
  • 1 Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom. , (United Kingdom)
  • 2 Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom. Electronic address: [email protected] , (United Kingdom)
Type
Published Article
Journal
Current opinion in chemical biology
Publication Date
Jun 01, 2019
Volume
50
Pages
101–110
Identifiers
DOI: 10.1016/j.cbpa.2019.03.001
PMID: 31004962
Source
Medline
Language
English
License
Unknown

Abstract

The β-lactams remain the most important antibacterials, but their use is increasingly compromised by resistance, importantly by β-lactamases. Although β-lactam and non-β-lactam inhibitors forming stable acyl-enzyme complexes with nucleophilic serine β-lactamases (SBLs) are widely used, these are increasingly susceptible to evolved SBLs and do not inhibit metallo-β-lactamases (MBLs). Boronic acids and boronate esters, especially cyclic ones, can potently inhibit both SBLs and MBLs. Vaborbactam, a monocyclic boronate, is approved for clinical use, but its β-lactamase coverage is limited. Bicyclic boronates rapidly react with SBLs and MBLs forming stable enzyme-inhibitor complexes that mimic the common anionic high-energy tetrahedral intermediates in SBL/MBL catalysis, as revealed by crystallography. The ability of boronic acids to 'morph' between sp2 and sp3 hybridisation states may help enable potent inhibition. There is limited structure-activity relationship information on the (bi)cyclic boronate inhibitors compared to β-lactams, hence scope for creativity towards new boron-based β-lactamase inhibitors/antibacterials. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

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