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

ABSTRACT: ?-Lactamases enable resistance to almost all ?-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-?-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent ?-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-?-lactamases, and which could also have antimicrobial activity through inhibition of PBPs.

SUBMITTER: Brem J 

PROVIDER: S-EPMC4979060 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Brem Jürgen J   Cain Ricky R   Cahill Samuel S   McDonough Michael A MA   Clifton Ian J IJ   Jiménez-Castellanos Juan-Carlos JC   Avison Matthew B MB   Spencer James J   Fishwick Colin W G CW   Schofield Christopher J CJ  

Nature communications 20160808

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 inhi  ...[more]

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