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 ␤-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.The carbapenem BMS-181139 has a broad antipseudomonal spectrum. In addition to Pseudomonas aeruginosa, the geometric mean MICs and MICs at which 90% of strains tested are inhibited (MIC 90 s) of BMS-181139 for 10 non-aeruginosa Pseudomonas species were Յ4 g/ml (14). Data from this study indicated that BMS-181139 was also active against imipenemresistant, clinical isolates of P. aeruginosa. Unlike the carbapenem meropenem, which has diminished activity against imipenem-resistant strains of P. aeruginosa (39), the activity of BMS-181139 against these strains was unaffected.Essentially all imipenem-resistant P. aeruginosa isolates produce low or undetectable levels of the porin protein D2 (2,8,21,33,35,38), suggesting its role in the permeation of imipenem across the outer membrane. The D2 channel was shown to facilitate the specific permeation of basic amino acids and, because of their structural similarities to basic amino acids, also imipenem and meropenem (36). It has been suggested that at low concentrations, imipenem penetrates primarily through the D2 channel but as the drug concentration increases, it is also transported through nonspecific porin channels (35,36). In a D2-deficient P. aeruginosa strain, stably derepressed production of ␤-lactamase leads to even higher levels of resistance to imipenem (17).Meropenem is less active against imipenem-resistant strains of P. ...

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa

“…Trias and Nikaido (10) suggested that the permeation of known carbapenems and basic amino acids through the D2 channel is due to their structural similarities. Imipenem, meropenem, biapenem, panipenem, and BO-2727 contain basic (positively charged) substituents at position 2 of the carbapenem (4). BMS-181139, on the other hand, lacks a basic group at position 2, which is consistent with its lack of dependence on D2 (4).…”

“…Unlike other known carbapenems, the new carbapenem BMS-181139 is equally active against D2-sufficient and D2-deficient strains of Pseudomonas aeruginosa (4). This suggests that BMS-181139 uptake in pseudomonads is via a pathway other than D2.…”

“…Since BMS-181139 activity is independent of porin protein D2, its MICs for P. aeruginosa were not affected by basic amino acids (4). BMY 45742, BMY 45047, and BMY 44896 are derivatives of imipenem, meropenem, and BMS-182880, respectively, with the former group of compounds containing a sec- ond basic group at position 1.…”

“…We determined their dependence on porin protein D2 by testing carbapenem derivatives containing a basic group(s) at position 6, 1, and/or 2. This was assessed by determining the activities of carbapenems against D2-sufficient and D2-deficient isogenic pairs and their activities against BMS-181139-resistant mutants believed to have diminished permeation through the non-D2 pathway (4). The effect of basic amino acids on the antipseudomonal activities of these carbapenems was also measured.…”

Pseudomonas aeruginosa multirresistente: um problema endêmico no Brasil

“…A presença de OprD, também denominada porina D2, tem sido amplamente investigada, uma vez que a ausência ou mesmo a expressão reduzida do gene oprD, codificador dessa porina, tem contribuído para a resistência aos carbapenêmicos, especialmente IPM (Tabela 2) (23,29,54,75,(115)(116)(117)120) . Devido à falta de consenso sobre a caracterização dessa proteína com determinado peso molecular, podemos encontrar relatos da ausência de proteínas OprD de 42 até 54 kDa (23,52,55,69,73,75,103,120) com fenótipos IPM resistentes. De fato, existem relatos que indicam a existência de homólogos da proteína OprD, o que pode gerar produtos de expressão de tamanhos diferenciados (76,100,101) .…”