Fung-Tomc J C, Huczko E, Banville J, Ménard M, Kolek B, Gradelski E, Kessler R E, Bonner D P
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492, USA.
Antimicrob Agents Chemother. 1995 Feb;39(2):394-9. doi: 10.1128/AAC.39.2.394.
A number of carbapenem derivatives were examined to determine the structure-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeruginosa. As suggested by J. Trias and H. Nikaido (Antimicrob. Agents Chemother. 34:52-57, 1990), carbapenem derivatives, such as imipenem and meropenem, containing a sole basic group at position 2 of the molecule utilize the D2 channel for permeation through the outer membrane of pseudomonads; they are more active against D2-sufficient strains of P. aeruginosa. Our results indicated that carbapenems with a basic group at position 1 or 6 of the molecule did not depend on the D2 channel for activity; i.e. they were equally active against D2-sufficient and D2-deficient pseudomonal strains. However, addition of a basic group at position 1 or 6 of a carbapenem derivative already containing a basic group at position 2 resulted in its lack of dependency on the D2 pathway. Comparison between meropenem and its 1-guanidinoethyl derivative, BMY 45047, indicated that they differed in their dependence on D2; while meropenem required the D2 channel for uptake, BMY 45047 activity was independent of D2. Meropenem and BMY 45047 had similar affinities for the penicillin-binding proteins of P. aeruginosa. However, BMY 45047 and meropenem differed in the morphological changes that they induced in pseudomonal cells. While meropenem induced filamentation, BMY 45047 induced filaments only in BMS-181139-resistant mutants and not in imipenem-resistant mutants or in carbapenem-susceptible P. aeruginosa strains. These results suggested that in Mueller-Hinton medium the uptake of BMY 45047 through the non-D2 pathway is more rapid than that of meropenem through the D2 porin. In summary, the presence of a basic group at position 2 of a carbapenem is important for its preferential uptake by the D2 channel. However the addition of a basic group at position 1 or 6 of a carbapenem already containing a basic group at position 2 dissociates its necessity for porin protein D2 for activity.
研究了多种碳青霉烯衍生物，以确定其对铜绿假单胞菌发挥活性时依赖孔蛋白D2所需的构效关系。正如J. Trias和H. Nikaido所指出的（《抗菌药物与化疗》34:52 - 57, 1990），碳青霉烯衍生物，如亚胺培南和美罗培南，在分子的2位含有一个唯一的碱性基团，它们利用D2通道穿过假单胞菌的外膜；它们对D2充足的铜绿假单胞菌菌株更具活性。我们的结果表明，在分子的1位或6位含有碱性基团的碳青霉烯类药物的活性不依赖于D2通道；即它们对D2充足和D2缺陷的假单胞菌菌株具有同等活性。然而，在已经在2位含有碱性基团的碳青霉烯衍生物的1位或6位添加碱性基团会导致其对D2途径的依赖性丧失。美罗培南与其1 - 胍基乙基衍生物BMY 45047的比较表明，它们对D2的依赖性不同；美罗培南需要D2通道进行摄取，而BMY 45047的活性不依赖于D2。美罗培南和BMY 45047对铜绿假单胞菌的青霉素结合蛋白具有相似的亲和力。然而，BMY 45047和美罗培南在它们诱导假单胞菌细胞形态变化方面有所不同。美罗培南诱导丝状化，而BMY 45047仅在对BMS - 181139耐药的突变体中诱导丝状化，在对亚胺培南耐药的突变体或对碳青霉烯敏感的铜绿假单胞菌菌株中则不诱导。这些结果表明，在穆勒 - 欣顿培养基中，BMY 45047通过非D2途径的摄取比美罗培南通过D2孔蛋白的摄取更快。总之，碳青霉烯类药物在2位存在碱性基团对其通过D2通道的优先摄取很重要。然而，在已经在2位含有碱性基团的碳青霉烯类药物的1位或6位添加碱性基团会使其对孔蛋白D2发挥活性的必要性丧失。
