The stability of meropenem in the presence of renal dehydropeptidase I (DHP-I) varied extremely with the animal source of the enzyme. Meropenem, compared with imipenem, was rather easily hydrolyzed by DHP-Is from mice, rabbits, and monkeys, while it showed a higher resistance to guinea pig and beagle dog DHP-Is. In addition, meropenem was four times more resistant than imipenem to human DHP-I. The 1 beta-methyl substituent on carbapenems, i.e., meropenem and 1 beta-methyl imipenem, made them considerably more resistant to mouse and swine DHP-Is than the 1-unsubstituted derivatives are.
The neurotoxicity of meropenemwas muchlower than that of both imipenemand panipenem after intraventricular administration to mice. To clarify the majorstructural features responsible for the induction of convulsions by carbapenemantibiotics, the structure-activity relationship on convulsant activity was investigated in iV-acetyl-2-pyrroline and cyclopentene derivatives which correspond to the 5-membered ring containing the C-2 side chain of carbapenem antibiotics. Among these derivatives, compoundswith strong basicity in the side chain showed convulsant activity similar to that of the parent carbapenem compounds. In addition to the strength of the basicity of the amino group, the distance from the carboxyl to the amino group and steric crowding around the amino group also appeared to play an important role in the induction of convulsions. The results of gammaaminobutyric acid (GABAA) receptor binding assays indicated that the induction of convulsions was caused predominantly by the inhibition of GABAA-mediatedinhibitory transmission. However, the in vivo convulsant activity of some of these compoundsdid not correlate with their in vitro inhibitory effect on GABAA receptor binding.
Weinvestigated the binding affinities of SM-7338 for penicillin-binding proteins (PBPs) and the morphological changes induced by it compared with those ofimipenem. Both SM-7338and imipenem had the highest binding affinities for PBP-2 of Escherichia coli, which were in good agreement with the primary morphological response of spherical cell formation. SM-7338also showed high affinities for PBP-1A, -IBs, and -3, and imipenem showed high affinities for PBP-1Aand -IBs but not for PBP-3. At 4-fold MIC, SM-7338 induced a indeterminate form, whereas imipenem did not. This may be due to the higher affinity of SM-7338 for PBP-3 compared to that of imipenem. Against Pseudomonas aeruginosa, SM-7338 had very high affinities for PBP-2 and -3, and imipenem had higher affinities for PBP-2 and -1A. SM-7338 induced this organism to filamentous cells at a concentration lower than its MIC, bulge cells at 2-fold MIC, and spherical cells at 4-fold MIC, while imipenem principally induced round cell formation at each concentration. These morphological differences in P. aeruginosa may be due to the differences in binding profiles to PBPs. Wealso studied the affinities for PBPs using radioactive SM-7338. The data obtained supported these results.Many new /Mactam antimicrobial agents have been introduced into clinical practice. Recently, non-traditional /Mactam antibiotics have been developed; one class which has been of particular interest is the carbapenems. Discovery of thienamycin1}, the antibiotic produced by Streptomyces cattleya, has taken the lead in opening the newera of /Mactamagents, the carbapenems. Subsequently a numberof carbapenems have been discovered and some of them were chemically synthesized, however, none have been available for clinical use except imipenem, the A^-formimidoyl derivative of thienamycin. SM-7338 a new carbapenem, which differs chemically from imipenem, has a methyl group at 4 position and carries a proline derivative on the 3-sulfur instead of the formimidoylaminoethyl group in imipenem. SM-7338 has a strong activity against Gram-positive and Gram-negative bacteria compared with other /Mactams2~7). The binding affinities of thienamycin and imipenem for penicillin-binding proteins (PBPs) of Escherichia coli and these effects on the shapes of the cells have been previously studied8~10). In E. coli PBPshave been knownto play essential roles in the maintenance of rod shape, septum formation, and functioning in the peptidoglycan biosynthesis, and so onll " 14*. The PBPs in Pseudomonas aeruginosa are presumed to have similar roles15).In this paper we examined the mode of action of SM-7338compared with imipenem from the viewpoint of affinities for PBPs and morphological changes, and we reported the difference ofmorphological responses between E. coli and P. aeruginosa induced by SM-7338whereas the same morphological changes were observed by imipenem.
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