ACTIVITY OF CARBAPENEM BMS-181139 AGAINST PSEUDOMONAS-AERUGINOSA IS NOT DEPENDENT ON PORIN PROTEIN D2

The broad antipseudomonal spectrum of the carbapenem BMS-181139 includ es clinical strains and laboratory mutants of Pseudomonas aeruginosa t hat are resistant to imipenem. Unlike other known carbapenems (meropen em, panipenem, biapenem, and BO-2727), which have reduced activity aga inst imipenem-resistant strains of P. aeruginosa, BMS-181139 was equal ly active against imipenem-susceptible (D2-sufficient) and imipenem-re sistant (D2-deficient) strains. Conversely, imipenem and meropenem act ivities were the same against the susceptible parental strains and the ir BMS-181139-resistant mutants. Whereas basic amino acids antagonized the antipseudomonal activities of imipenem and meropenem, they had no effect on the activity of BMS-181139, These results suggest that the uptake of BMS-181139 into pseudomonal cells occurs by a non-D2 pathway . Compared with imipenem and meropenem, BMS-181139 may have a slightly higher affinity for penicillin-binding protein 2 (PBP-2) of P. aerugi nosa. The rates of resistance development to imipenem, meropenem, and BMS-181139 in P. aeruginosa strains were similar; resistance occurred at frequencies of approximately 10(-7) to 10(-8). Resistance to BMS-18 1139 in P. aeruginosa is presumed to be caused by its diminished perme ability since no change in their penicillin-binding protein affinities or beta-lactamase levels could be detected. In summary, EMS-181139 is a new carbapenem which differs from other known carbapenems in its la ck of cross-resistance with imipenem. This difference could be explain ed by the permeation of BMS-181139 through a non-D2 channel, compared to the preferential uptake of other carbapenems by the D2 porin.