Structure-activity relationships of carbapenems to the antagonism of the antipseudomonal activity of other beta-lactam agents and to the beta-lactamase inducibility in Pseudomonas aeruginosa: effects of 1beta-methyl group and C-2 side chain.
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.
Kanazawa
K
K
Sumitomo Pharmaceuticals Research Center, Konohana, Osaka, Japan.
Nouda
H
H
Sumita
Y
Y
Sunagawa
M
M
D015780:Carbapenems / Q000737:chemistry / Q000494:pharmacology*; D002442:Ceftazidime / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002511:Cephalosporins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D008745:Methylation; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000096:biosynthesis
D015780:Carbapenems; D002511:Cephalosporins; D065093:beta-Lactamase Inhibitors; D002442:Ceftazidime; D001618:beta-Lactamases