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

• Published in: Journal of antimicrobial chemotherapy 2000-03, Vol.45 (3), p.271-276
• Main Authors: NAGANO, R, ADACHI, Y, HASHIZUME, T, MORISHIMA, H
• Format: Article
• Language: English
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus cereus; Bacteroides fragilis; Biological and medical sciences; Medical sciences; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Serratia marcescens; Stenotrophomonas maltophilia
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/45.3.271

IMP-1 beta -lactamase, a class B zinc metallo-enzyme encoded by the transferable bla sub(IMP) gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111,225 is a novel 1 beta -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 sub(i) of 0.18 mu M 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 sub(m) values of 11, 10 and 148 mu M. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the beta -lactamase.