Grand Valley State University, Cell and Molecular Biology, Grand Rapids, MI 49503
The b–lactamase is the most prevalent resistance mechanism to commonly prescribed b-lactam antibiotics. These enzymes hydrolyze the lactam ring that is crucial for the antibiotic to be effective. One way to overcome this resistance is to block the activity of this enzyme. Current clinical inhibitors for these enzymes also contain a lactam ring, allowing resistance to develop rapidly. Inhibitors that do not resemble β-lactams would require bacteria to develop novel resistance mechanisms. Previous research identified a novel, non-β-lactam inhibitor for the class C β-lactamase AmpC (3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid; KI 26 mM). In an effort to improve the binding affinity of this inhibitor, a series of derivatives were synthesized. Each compound was tested for inhibition of the class C b–lactamase AmpC, and the x-ray crystal structures of several inhibitors in complex with AmpC were determined. Data obtained from these complexes provides information on binding site interactions in the active site and may be useful for future drug discovery against AmpC.
[Abstract (DOC)]