In vitro antibacterial activity and mechanism of action of J-111,225, a novel 1beta-methylcarbapenem, against transferable IMP-1 metallo-beta-lactamase producers

J Antimicrob Chemother. 2000 Mar;45(3):271-6. doi: 10.1093/jac/45.3.271.

Abstract

IMP-1 beta-lactamase, a class B zinc metallo-enzyme encoded by the transferable bla(IMP) gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111, 225 is a novel 1beta-methylcarbapenem with a structurally unique side chain comprising a trans-3,5-disubstituted pyrrolidinylthio moiety at the C2 position. It inhibited 17 Serratia marcescens and two Pseudomonas aeruginosa IMP-1-producing clinical isolates at a concentration of 32 mg/L (range 4-32 mg/L). It showed synergy with imipenem against IMP-1-producing S. marcescens BB5886 and P. aeruginosa GN17203 with minimal FIC indices of 0.38 and 0.5, respectively. J-111,225 was more resistant than imipenem to hydrolysis by class B metallo-beta-lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a K(i) of 0.18 microM when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B beta-lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective K(m) values of 11, 10 and 148 microM. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the beta-lactamase.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacteria / drug effects*
  • Bacteria / enzymology*
  • Bacteroides fragilis / drug effects
  • Bacteroides fragilis / enzymology
  • Carbapenems / pharmacology*
  • Drug Therapy, Combination / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Imipenem / pharmacology
  • Microbial Sensitivity Tests
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology
  • Serratia marcescens / drug effects
  • Serratia marcescens / enzymology
  • Thienamycins / pharmacology
  • beta-Lactamase Inhibitors*

Substances

  • Anti-Bacterial Agents
  • Carbapenems
  • Enzyme Inhibitors
  • J 111225
  • Thienamycins
  • beta-Lactamase Inhibitors
  • Imipenem