Using steric hindrance to design new inhibitors of class C beta-lactamases

Chem Biol. 2002 Sep;9(9):971-80. doi: 10.1016/s1074-5521(02)00211-9.

Abstract

beta-lactamases confer resistance to beta-lactam antibiotics such as penicillins and cephalosporins. However, beta-lactams that form an acyl-intermediate with the enzyme but subsequently are hindered from forming a catalytically competent conformation seem to be inhibitors of beta-lactamases. This inhibition may be imparted by specific groups on the ubiquitous R(1) side chain of beta-lactams, such as the 2-amino-4-thiazolyl methoxyimino (ATMO) group common among third-generation cephalosporins. Using steric hindrance of deacylation as a design guide, penicillin and carbacephem substrates were converted into effective beta-lactamase inhibitors and antiresistance antibiotics. To investigate the structural bases of inhibition, the crystal structures of the acyl-adducts of the penicillin substrate amoxicillin and the new analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds in a catalytically incompetent conformation resembling that adopted by third-generation cephalosporins, demonstrating the transferability of such sterically hindered groups in inhibitor design.

Publication types

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

MeSH terms

  • Acylation
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Hydrolysis
  • Kinetics
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Conformation
  • Structure-Activity Relationship
  • beta-Lactam Resistance
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / classification
  • beta-Lactamases / metabolism
  • beta-Lactams

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • beta-Lactamases

Associated data

  • PDB/1LL9
  • PDB/1LLB