Format

Send to

Choose Destination
J Med Chem. 2014 Jun 26;57(12):5449-58. doi: 10.1021/jm5006572. Epub 2014 Jun 16.

Targeting class A and C serine β-lactamases with a broad-spectrum boronic acid derivative.

Author information

1
Department of Pharmaceutical Chemistry, University of California San Francisco , 600 16th Street San Francisco, California 94143-2240, United States.

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.

PMID:
24882105
PMCID:
PMC4079326
DOI:
10.1021/jm5006572
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center