Structure-activity Relationships of Carbapenems to the Antagonism of the Antipseudomonal Activity of Other /J-Lactam Agents and to the /J-Lactamase Inducibility in Pseudomonas aeruginosa: Effects of ljS-Methyl Group and C-2 Side Chain

The antagonism of the antipseudomonal activity of ceftazidime by meropenem(la) 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 /Mactamase-inducibility in P. aeruginosa. The antagonistic effect of la was less than that of desmethyl-meropenem (lb). Two other meropenem-analogues (3, 4), with the highly basic C-2 side chain, showed greater antagonistic effects than that of la, which has a weakly basic C-2 side chain. The /Mactamase-inducibility of la in P. aeruginosa was lower than those of 2a, lb and 4. These results indicated that the antagonism of the antipseudomonal activity of ceftazidime by carbapenems was due to the induction of /Mactamase in P. aeruginosa. As a result of the study on the structure-activity relationships, we clarified that the introduction ofa 1 j6-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 /Mactamase inducibility.