Structural basis of metallo-beta-lactamase, serine-beta-lactamase and penicillin-binding protein inhibition by cyclic boronates.
Brem, J., Cain, R., Cahill, S., McDonough, M.A., Clifton, I.J., Jimenez-Castellanos, J.C., Avison, M.B., Spencer, J., Fishwick, C.W., Schofield, C.J.(2016) Nat Commun 7: 12406-12406
- PubMed: 27499424 
- DOI: https://doi.org/10.1038/ncomms12406
- Primary Citation of Related Structures:  
5FQ9, 5FQB, 5FQC, 5J8X - PubMed 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.
Organizational Affiliation: 
Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.