Download MendeleyTargeting Class A and C Serine beta-Lactamases with a Broad-Spectrum Boronic Acid Derivative.
Tondi, D., Venturelli, A., Bonnet, R., Pozzi, C., Shoichet, B.K., Costi, M.P.(2014) J Med Chem 57: 5449-5458
- PubMed: 24882105
- DOI: https://doi.org/10.1021/jm5006572
- Primary Citation of Related Structures:
4LEN - PubMed Abstract:
Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies.
Organizational Affiliation:
Department of Pharmaceutical Chemistry, University of California San Francisco , 600 16th Street San Francisco, California 94143-2240, United States.
