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Nat Commun. 2016 Aug 8;7:12406. doi: 10.1038/ncomms12406.

Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates.

Author information

1
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
2
School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
3
School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.

Abstract

β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.

PMID:
27499424
PMCID:
PMC4979060
DOI:
10.1038/ncomms12406
[Indexed for MEDLINE]
Free PMC Article

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