title: Activity of carbapenem BMS-181139 against Pseudomonas aeruginosa is not dependent on porin protein D2.
abstract: The broad antipseudomonal spectrum of the carbapenem BMS-181139 includes clinical strains and laboratory mutants of Pseudomonas aeruginosa that are resistant to imipenem. Unlike other known carbapenems (meropenem, panipenem, biapenem, and BO-2727), which have reduced activity against imipenem-resistant strains of P. aeruginosa, BMS-181139 was equally active against imipenem-susceptible (D2-sufficient) and imipenem-resistant (D2-deficient) strains. Conversely, imipenem and meropenem activities were the same against the susceptible parental strains and their 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. aeruginosa. 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-181139 in P. aeruginosa is presumed to be caused by its diminished permeability since no change in their penicillin-binding protein affinities or beta-lactamase levels could be detected. In summary, BMS-181139 is a new carbapenem which differs from other known carbapenems in its lack of cross-resistance with imipenem. This difference could be explained by the permeation of BMS-181139 through a non-D2 channel, compared to the preferential uptake of other carbapenems by the D2 porin.
authors.affiliation: Department of Microbiology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Fung-Tomc
authors.forename: E
authors.initials: E
authors.lastname: Gradelski
authors.forename: B
authors.initials: B
authors.lastname: Kolek
authors.forename: B
authors.initials: B
authors.lastname: Minassian
authors.forename: M
authors.initials: M
authors.lastname: Pucci
authors.forename: R E
authors.initials: RE
authors.lastname: Kessler
authors.forename: D P
authors.initials: DP
authors.lastname: Bonner
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D001426:Bacterial Proteins; D015780:Carbapenems / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D004352:Drug Resistance, Microbial; D006146:Guanidines / Q000494:pharmacology*; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase / Q000378:metabolism; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases; D018272:Porins / Q000032:analysis*; D011550:Pseudomonas aeruginosa / Q000737:chemistry / Q000187:drug effects*; D001618:beta-Lactamases / Q000032:analysis
chemical_list: D000596:Amino Acids; C093179:BMS 181139; D001426:Bacterial Proteins; D015780:Carbapenems; D002352:Carrier Proteins; D006146:Guanidines; D046915:Penicillin-Binding Proteins; D018272:Porins; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase; D001618:beta-Lactamases