Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase.
beta-lactamases are the most widespread resistance mechanisms to beta-lactam antibiotics, and there is a pressing need for novel, non-beta-lactam drugs. A database of over 200,000 compounds was docked to the active site of AmpC beta-lactamase to identify potential inhibitors. Fifty-six compounds were tested, and three had K(i) values of 650 microM or better. The best of these, 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic acid, was a competitive noncovalent inhibitor (K(i) = 26 microM), which also reversed resistance to beta-lactams in bacteria expressing AmpC. The structure of AmpC in complex with this compound was determined by X-ray crystallography to 1.94 A 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.
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, 303 East Chicago Avenue, IL 60611, USA.
Rachel A
RA
Powers
Federica
F
Morandi
Brian K
BK
Shoichet
D000667:Ampicillin / Q000494:pharmacology; D000814:Aniline Compounds / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases
C467421:3-((4-chloroanilino)sulfonyl)thiophene-2-carboxylic acid; D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013876:Thiophenes; D065093:beta-Lactamase Inhibitors; D000667:Ampicillin; C048795:AmpC beta-lactamases; D001618:beta-Lactamases