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

Autor:	Brem J; Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK., Cain R; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK., Cahill S; Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK., McDonough MA; Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK., Clifton IJ; Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK., Jiménez-Castellanos JC; School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK., Avison MB; School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK., Spencer J; School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK., Fishwick CW; School of Chemistry, University of Leeds, Leeds LS2 9JT, UK., Schofield CJ; Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2016 Aug 08; Vol. 7, pp. 12406. Date of Electronic Publication: 2016 Aug 08.
DOI:	10.1038/ncomms12406
Abstrakt:	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.
Databáze:	MEDLINE
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