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

DOI: 10.1038/ncomms12406 DOI Help

Authors: Jurgen Brem (Department of Chemistry, University of Oxford) , Ricky Cain (School of Chemistry, University of Leeds) , Samuel Cahill (Department of Chemistry, University of Oxford) , Michael Mcdonough (Department of Chemistry, University of Oxford) , Ian J. Clifton (Department of Chemistry, University of Oxford) , Juan-carlos Jiménez-castellanos (School of Cellular and Molecular Medicine, University of Bristol) , Matthew B. Avison (School of Cellular and Molecular Medicine, University of Bristol) , James Spencer (School of Cellular and Molecular Medicine, University of Bristol) , Colin W. G. Fishwick (School of Chemistry, University of Leeds) , Christopher J. Schofield (Department of Chemistry, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 7

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 12346

Open Access Open Access

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.

Journal Keywords: Enzymes; Structural biology

Subject Areas: Medicine, Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
ncomms12406.pdf