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

IMP-1 -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 1 -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-1producing 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- -lactamases. In kinetic studies, J-111,225 inhibited the IMP-I enzyme with a Ki of 0.18 M when imipenem was used as a substrate. In contrast, J-111,225 was the substrate for hydrolysis by other class B -lactamases such as Bacteroides fragilis CcrA, Stenotrophomonas maltophilia L1 and Bacillus cereus type II enzyme with respective Km values of 11, 10 and 148 M. The greater antibacterial activity of J-111,225 against IMP-1-producing bacteria may result from its unique interaction with the -lactamase.