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Journal of Antimicrobial Chemotherapy (2000) 45, 271-276
© 2000 The British Society for Antimicrobial Chemotherapy

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

Rie Nagano*, Yuka Adachi, Terutaka Hashizume and Hajime Morishima

Banyu Tsukuba Research Institute, Okubo 3, Tsukuba 300-2611, Japan

IMP-1 ß-lactamase, a class B zinc metallo-enzyme encoded by the transferable blaIMP gene, is known to confer high-level resistance to carbapenems as well as to penicillins and cephalosporins. J-111,225 is a novel 1ß-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-ß-lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a Ki of 0.18 µM when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B ß-lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective Km values of 11, 10 and 148 µM. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the ß-lactamase.

* Corresponding author. Tel: +81-298-77-2000; Fax: +81-298-77-2029; E-mail: naganori{at}banyu.co.jp


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