Structure-Based Discovery of a Novel, Noncovalent Inhibitor of AmpC β-Lactamase

Abstractβ-lactamases are the most widespread resistance mechanisms to β-lactam antibiotics, and there is a pressing need for novel, non-β-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC β-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had Ki values of 650 μM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (Ki = 26 μM), which also reversed resistance to β-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 Å and reveals that the inhibitor interacts with key active-site residues in sites targeted in the docking calculation. Indeed, the experimentally determined conformation of the inhibitor closely resembles the prediction. The structure of the enzyme-inhibitor complex presents an opportunity to improve binding affinity in a novel series of inhibitors discovered by structure-based methods