Kanazawa K, Nouda H, Sumita Y, Sunagawa M
Sumitomo Pharmaceuticals Research Center, Konohana, Osaka, Japan.
J Antibiot (Tokyo). 1999 Feb;52(2):142-9. doi: 10.7164/antibiotics.52.142.
The antagonism of the antipseudomonal activity of ceftazidime by meropenem (1a) was much less than those by imipenem (2a) and panipenem (2b). To reveal the major structural features of carbapenem compounds responsible for the antagonism, we investigated the structure-activity relationships of carbapenems to their antagonism of the antipseudomonal activity of ceftazidime and to their beta-lactamase-inducibility in P. aeruginosa. The antagonistic effect of 1a was less than that of desmethyl-meropenem (1b). Two other meropenem-analogues (3, 4), with the highly basic C-2 side chain, showed greater antagonistic effects than that of 1a, which has a weakly basic C-2 side chain. The beta-lactamase-inducibility of 1a in P. aeruginosa was lower than those of 2a, 1b and 4. These results indicated that the antagonism of the antipseudomonal activity of ceftazidime by carbapenems was due to the induction of beta-lactamase in P. aeruginosa. As a result of the study on the structure-activity relationships, we clarified that the introduction of a 1beta-methyl group and/or the reduction of the basicity (cationic character) of the C-2 side chain in carbapenem skeleton decreased the antagonistic effect of carbapenems on the antipseudomonal activity of ceftazidime resulted mainly from the decreasing the beta-lactamase inducibility.
美罗培南（1a）对头孢他啶抗假单胞菌活性的拮抗作用远小于亚胺培南（2a）和帕尼培南（2b）。为揭示碳青霉烯类化合物中导致这种拮抗作用的主要结构特征，我们研究了碳青霉烯类化合物对头孢他啶抗假单胞菌活性的拮抗作用及其在铜绿假单胞菌中诱导β-内酰胺酶能力的构效关系。1a的拮抗作用小于去甲基美罗培南（1b）。另外两种具有高碱性C-2侧链的美罗培南类似物（3、4），其拮抗作用比具有弱碱性C-2侧链的1a更强。1a在铜绿假单胞菌中诱导β-内酰胺酶的能力低于2a、1b和4。这些结果表明，碳青霉烯类化合物对头孢他啶抗假单胞菌活性的拮抗作用是由于其在铜绿假单胞菌中诱导β-内酰胺酶所致。通过对构效关系的研究，我们阐明了在碳青霉烯骨架中引入1β-甲基和/或降低C-2侧链的碱性（阳离子特性）可降低碳青霉烯类化合物对头孢他啶抗假单胞菌活性的拮抗作用，这主要是由于β-内酰胺酶诱导能力降低所致。
