Structure-based discovery of a novel, noncovalent inhibitor of AmpC beta-lactamase

Structure. 2002 Jul;10(7):1013-23. doi: 10.1016/s0969-2126(02)00799-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ampicillin / pharmacology
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins*
  • Crystallography, X-Ray
  • Drug Design
  • Drug Resistance, Bacterial
  • Drug Synergism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / drug effects
  • Microbial Sensitivity Tests
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology
  • beta-Lactamase Inhibitors*
  • beta-Lactamases


  • 3-((4-chloroanilino)sulfonyl)thiophene-2-carboxylic acid
  • Aniline Compounds
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Thiophenes
  • beta-Lactamase Inhibitors
  • Ampicillin
  • AmpC beta-lactamases
  • beta-Lactamases

Associated data

  • PDB/1L2S