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

to be developed. -lactamases are the most widespread resistance Several classes of non-lactam inhibitors of -lactamechanisms to -lactam antibiotics, and there is a mases have been identified. Transition-state analog inpressing need for novel, non-lactam drugs. A datahibitors (Figure 1C), such as boronic acids and phosphobase of over 200,000 compounds was docked to the nates, inhibit both class A and class C -lactamases active site of AmpC -lactamase to identify potential [4, 5]. Much effort has been devoted to improving the inhibitors. Fifty-six compounds were tested, and three binding affinities of these molecules [3, 6–9]. One conhad Ki values of 650 M or better. The best of these, cern with both types of molecules is that they form 3-[(4-chloroanilino)sulfonyl]thiophene-2-carboxylic covalent adducts with activated serine nucleophiles, poacid, was a competitive noncovalent inhibitor (Ki 26 tentially reducing their selectivity versus other serine M), which also reversed resistance to -lactams in active enzymes, such as serine proteases. A noncovabacteria expressing AmpC. The structure of AmpC in lent inhibitor may be better suited as a candidate lead complex with this compound was determined by X-ray in drug development for this reason. crystallography to 1.94 Å and reveals that the inhibitor In an effort to identify a novel, noncovalent inhibitor interacts with key active-site residues in sites targeted of AmpC -lactamase, we used a structure-based apin the docking calculation. Indeed, the experimentally proach, beginning with a consensus map of “hot spots” determined conformation of the inhibitor closely reon the enzyme. The consensus map was recently consembles the prediction. The structure of the enzymestructed from crystal structures of AmpC in complexes inhibitor complex presents an opportunity to improve with 13 different ligands [10]. This map was used as a binding affinity in a novel series of inhibitors discovtemplate in a molecular docking calculation to screen ered by structure-based methods. a database of over 200,000 small molecules for comple-