Antibiotic Sensitization Using Biphenyl Tetrazoles as Potent Inhibitors of Bacteroides Fragilis Metallo-Beta-Lactamase

Chem Biol. 1998 Apr;5(4):185-96. doi: 10.1016/s1074-5521(98)90632-9.

Abstract

Background: High level resistance to carbapenem antibiotics in gram negative bacteria such as Bacteroides fragilis is caused, in part, by expression of a wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive form. Co-administration of metallo-beta-lactamase inhibitors to resistant bacteria is expected to restore the antibacterial activity of carbapenems.

Results: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive inhibitors of metallo-beta-lactamase identified through screening and predicted using molecular modeling of the enzyme structure. The X-ray crystal structure of the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the inhibitor interacts directly with one of the two zinc atoms in the active site, replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by BPTs in vitro correlates well with antibiotic sensitization of resistant B. fragilis.

Conclusions: BPT inhibitors can sensitize a resistant B. fragilis clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem or penicillin G but not to rifampicin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteroides fragilis / drug effects*
  • Bacteroides fragilis / enzymology
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Carbapenems / metabolism*
  • Carbapenems / pharmacology
  • Crystallography, X-Ray
  • Drug Interactions
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Models, Molecular
  • Protein Conformation
  • Structure-Activity Relationship
  • Tetrazoles / chemistry
  • Tetrazoles / pharmacology*
  • beta-Lactam Resistance
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry
  • beta-Lactamases / drug effects
  • beta-Lactamases / metabolism

Substances

  • Biphenyl Compounds
  • Carbapenems
  • Enzyme Inhibitors
  • L 159906
  • Tetrazoles
  • beta-Lactamase Inhibitors
  • beta-Lactamases