Abstract
Cephamycins, which have a methoxy group at the 7 alpha position of their cephalosporin nuclei, were highly stable against hydrolysis by a beta-lactamase purified from a clinical isolate of Morganella morganii, whereas their 7 alpha-H analogs were rapidly hydrolyzed by the enzyme. The high stability of the cephamycins was not due to their low affinity for the enzyme, since the cephamycins strongly inhibited the enzyme in a competitive manner. In cases in which the 7 alpha-methoxy group was substituted by OC2H5, SCH3, CN, or CH3 groups, the substituted compounds still showed high stability against enzymatic hydrolysis but significantly reduced both their affinities for the enzyme and their antibacterial activities. These 7 alpha-substituted cephalosporins, except for cephamycins, also had greatly reduced affinities for target proteins, i.e., penicillin-binding proteins, of beta-lactam antibiotics. Therefore, the 7 alpha position of cephalosporins was considered to play an important role in both beta-lactamase stability and antibacterial activity.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Daoust D. R., Onishi H. R., Wallick H., Hendlin D., Stapley E. O. Cephamycins, a new family of beta-lactam antibiotics: antibacterial activity and resistance to beta-lactamase degradation. Antimicrob Agents Chemother. 1973 Feb;3(2):254–261. doi: 10.1128/aac.3.2.254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujii-Kuriyama Y., Yamamoto M., Sugawara S. Purification and properties of beta-lactamase from Proteus morganii. J Bacteriol. 1977 Sep;131(3):726–734. doi: 10.1128/jb.131.3.726-734.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakao H., Yanagisawa H., Ishihara S., Nakayama E., Ando A., Nakazawa J., Shimizu B., Kaneko M., Nagano M., Sugawara S. Semisynthetic cephamycins. II. Structure-activity studies related to cefmetazole (CS-1170). J Antibiot (Tokyo) 1979 Apr;32(4):320–329. doi: 10.7164/antibiotics.32.320. [DOI] [PubMed] [Google Scholar]
- Ohya S., Fujii-Kuriyama Y., Yamamoto M., Sugawara S. Purification and some properties of beta-lactamases from Proteus rettgeri and Proteus inconstans. Microbiol Immunol. 1980;24(9):815–824. doi: 10.1111/j.1348-0421.1980.tb02886.x. [DOI] [PubMed] [Google Scholar]
- Ohya S., Utsui Y., Sugawara S., Yamazaki M. Penem derivatives: beta-lactamase stability and affinity for penicillin-binding proteins in Escherichia coli. Antimicrob Agents Chemother. 1982 Mar;21(3):492–497. doi: 10.1128/aac.21.3.492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohya S., Yamazaki M., Sugawara S., Matsuhashi M. Penicillin-binding proteins in Proteus species. J Bacteriol. 1979 Jan;137(1):474–479. doi: 10.1128/jb.137.1.474-479.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohya S., Yamazaki M., Sugawara S., Tamaki S., Matsuhashi M. New cephamycin antibiotic, CS-1170: binding affinity to penicillin-binding proteins and inhibition of peptidoglycan cross-linking reactions in Escherichia coli. Antimicrob Agents Chemother. 1978 Nov;14(5):780–785. doi: 10.1128/aac.14.5.780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Richmond M. H. Beta-lactam antibiotics and beta-lactamases: two sides of a continuing story. Rev Infect Dis. 1979 Jan-Feb;1(1):30–38. [PubMed] [Google Scholar]
- Richmond M. H., Sykes R. B. The beta-lactamases of gram-negative bacteria and their possible physiological role. Adv Microb Physiol. 1973;9:31–88. doi: 10.1016/s0065-2911(08)60376-8. [DOI] [PubMed] [Google Scholar]