Mechanism of enhanced antipseudomonal activity of BO-2727, a new injectable 1-beta-methyl carbapenem
Mechanism of enhanced antipseudomonal activity of BO-2727, a new injectable 1-beta-methyl carbapenem
复制标题
新型注射用1-β-甲基碳青霉烯类BO-2727增强抗假单胞菌活性的机制
DOI：
10.1128/aac.39.3.702
复制
发表时间：
1995
影响因子：
4.9
通讯作者：
M. Sanada
中科院分区：
文献类型：
--
作者：
N. Hazumi;A. Fuse;K. Matsuda;Terutaka Hashizume;M. Sanada
通过使用源自β-内酰胺酶缺陷型铜绿假单胞菌PAO 4089（布拉伊blaP）的一组四种同基因菌株，研究BO-2727对亚胺培南耐药铜绿假单胞菌的增强活性的机制。与BO-2727和美罗培南相比，布拉伊和blaP突变的互补赋予比阿培南、帕尼培南和亚胺培南更大的耐药性，最显著的是在外膜蛋白D2缺陷型菌株中。对比阿培南、帕尼培南和亚胺培南较高水平的耐药性可通过β-内酰胺酶缓慢但显著的水解来解释，而对BO-2727和美罗培南的耐药性水平降低可归因于它们在高水平β-内酰胺酶存在下的稳定性以及它们仅引起低水平β-内酰胺酶诱导的事实。还注意到，B 0 -2727对β-内酰胺酶缺陷型菌株的活性受D2孔蛋白损失的影响小于美罗培南，表明B 0 -2727与美罗培南相比可克服由D2损失引起的内在抗性。此外，体外耐药性比较研究表明，BO-2727和美罗培南选择的耐药细胞少于其他碳青霉烯类。总之，BO-2727对亚胺培南耐药铜绿假单胞菌表现出改善的活性，这可能是因为其能够克服D2孔蛋白和β-内酰胺酶水解的损失。
The mechanism of the enhanced activity of BO-2727 against imipenem-resistant Pseudomonas aeruginosa was studied by using a set of four isogenic strains derived from beta-lactamase-deficient P. aeruginosa PAO4089 (blaJ blaP). Complementation of the blaJ and blaP mutations conferred greater resistance to biapenem, panipenem, and imipenem than to BO-2727 and meropenem, most notably in the outer membrane protein D2-deficient strain. The higher levels of resistance to biapenem, panipenem, and imipenem can be explained by the slow but significant hydrolysis by beta-lactamase, whereas the reduced levels of resistance to BO-2727 and meropenem would be attributable to their stability in the presence of high levels of beta-lactamase and the fact that they cause only low induction of beta-lactamase. It is also noted that the activity of BO-2727 against the beta-lactamase-deficient strain was less affected by the loss of the D2 porin than was that of meropenem, indicating that BO-2727 in comparison with meropenem can overcome an intrinsic resistance caused by the loss of D2. Moreover, comparative in vitro resistance studies have shown that BO-2727 and meropenem selected fewer resistant cells than other carbapenems. In conclusion, BO-2727 exhibited improved activity against imipenem-resistant P. aeruginosa, probably because of its ability to overcome loss of the D2 porin and beta-lactamase hydrolysis.