Fung-Tomc J C, Gradelski E, Kolek B, Minassian B, Pucci M, Kessler R E, Bonner D P
Department of Microbiology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Antimicrob Agents Chemother. 1995 Feb;39(2):386-93. doi: 10.1128/AAC.39.2.386.
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.
碳青霉烯类药物BMS - 181139具有广泛的抗铜绿假单胞菌谱，包括对亚胺培南耐药的铜绿假单胞菌临床菌株和实验室突变株。与其他已知的碳青霉烯类药物（美罗培南、帕尼培南、比阿培南和BO - 2727）不同，这些药物对亚胺培南耐药的铜绿假单胞菌活性降低，而BMS - 181139对亚胺培南敏感（D2充足）和亚胺培南耐药（D2缺陷）菌株的活性相同。相反，亚胺培南和美罗培南对敏感亲代菌株及其BMS - 181139耐药突变体的活性相同。碱性氨基酸可拮抗亚胺培南和美罗培南的抗铜绿假单胞菌活性，但对BMS - 181139的活性没有影响。这些结果表明，BMS - 181139进入铜绿假单胞菌细胞是通过非D2途径。与亚胺培南和美罗培南相比，BMS - 181139对铜绿假单胞菌青霉素结合蛋白2（PBP - 2）的亲和力可能略高。铜绿假单胞菌菌株对亚胺培南、美罗培南和BMS - 181139的耐药率相似；耐药发生频率约为10^(-7)至10^(-8)。推测铜绿假单胞菌对BMS - 181139耐药是由于其通透性降低，因为未检测到其青霉素结合蛋白亲和力或β - 内酰胺酶水平的变化。总之，BMS - 181139是一种新型碳青霉烯类药物，与其他已知碳青霉烯类药物的不同之处在于它与亚胺培南不存在交叉耐药性。与其他碳青霉烯类药物通过D2孔蛋白优先摄取相比，这种差异可以用BMS - 181139通过非D2通道渗透来解释。
