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. 1981 Jan;19(1):1–7. doi: 10.1128/aac.19.1.1

Role of the 7 alpha-methoxy and side-chain carboxyl of moxalactam in beta-lactamase stability and antibacterial activity.

K Murakami, T Yoshida
PMCID: PMC181347  PMID: 6454378

Abstract

The effects of the alpha-carboxyl of the phenylmalonyl side chain and the 7 alpha-methoxy group in moxalactam (6059-S) (7 beta-[2-carboxy-2-(4-hydroxyphenyl) acetamido]-7 alpha-methoxy-3[[(1-methyl-1H-tetrazol-5-y])thio] methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid) and in the 1-sulfur congener on the stability to beta-lactamase were investigated by spectrophotometric and microbiological assays. The 7 alpha-methoxy substituent stabilized the compounds against penicillinase hydrolysis, and the alpha-carboxyl group stabilized them against cephalosporinase. An exception is the beta-lactamase produced by Proteus vulgaris, an inducible cephalosporinase, which hydrolyzed compounds having the alpha-carboxyl group but not those having the 7 alpha-methoxy group. Both substituents exerted their stabilizing effects independently, and compounds with both substituents, e.g., moxalactam (6059-S) and its 1-sulfur congener, were resistant to both penicillinases and cephalosporinases. The stabilization of the compounds to beta-lactamase hydrolysis improved their antibacterial activity against beta-lactamase-producing strains.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boyd D. B. Transition state structures of a dipeptide related to the mode of action of beta-lactam antibiotics. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5239–5243. doi: 10.1073/pnas.74.12.5239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. CROMPTON B., JAGO M., CRAWFORD K., NEWTON G. G., ABRAHAM E. P. Behaviour of some derivatives of 7-aminocephalosporanic acid and 6-aminopenicillanic acidas substrates, inhibitors and inducers of penicillinases. Biochem J. 1962 Apr;83:52–63. doi: 10.1042/bj0830052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Datta N., Richmond M. H. The purification and properties of a penicillinase whose synthesis is mediated by an R-factor in Escherichia coli. Biochem J. 1966 Jan;98(1):204–209. doi: 10.1042/bj0980204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fu K. P., Neu H. C. beta-lactamase stability of HR 756, a novel cephalosporin, compared to that of cefuroxime and cefoxitin. Antimicrob Agents Chemother. 1978 Sep;14(3):322–326. doi: 10.1128/aac.14.3.322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Hennessey T. D., Richmond M. H. The purification and some properties of a beta-lactamase (cephalosporinase) synthesized by Enterobactercloacae. Biochem J. 1968 Sep;109(3):469–473. doi: 10.1042/bj1090469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hou J. P., Poole J. W. Kinetics of -lactamase inactivation of penicillins I: effect of side-chain structure, ionic strength, pH, and temperature. J Pharm Sci. 1973 May;62(5):783–788. doi: 10.1002/jps.2600620516. [DOI] [PubMed] [Google Scholar]
  7. Indelicato J. M., Wilham W. L. Effect of 6-alpha substitution in penicillins and 7-beta substitution in cephalosporins upon beta-lactam reactivity. J Med Chem. 1974 May;17(5):528–529. doi: 10.1021/jm00251a012. [DOI] [PubMed] [Google Scholar]
  8. JANSSON J. A. A DIRECT SPECTROPHOTOMETRIC ASSAY FOR PENICILLIN BETA-LACTAMASE (PENICILLINASE). Biochim Biophys Acta. 1965 Apr 26;99:171–172. doi: 10.1016/s0926-6593(65)80018-2. [DOI] [PubMed] [Google Scholar]
  9. Jack G. W., Richmond M. H. A comparative study of eight distinct beta-lactamases synthesized by gram-negative bacteria. J Gen Microbiol. 1970 Apr;61(1):43–61. doi: 10.1099/00221287-61-1-43. [DOI] [PubMed] [Google Scholar]
  10. Nagarajan R., Boeck L. D., Gorman M., Hamill R. L., Higgens C. E., Hoehn M. M., Stark W. M., Whitney J. G. Beta-lactam antibiotics from Streptomyces. J Am Chem Soc. 1971 May 5;93(9):2308–2310. doi: 10.1021/ja00738a035. [DOI] [PubMed] [Google Scholar]
  11. Narisada M., Yoshida T., Onoue H., Ohtani M., Okada T., Tsuji T., Kikkawa I., Haga N., Satoh H., Itani H. Synthetic studies on beta-lactam antibiotics. Part 101. Synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7alpha-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-S) and its related 1-oxacephems. J Med Chem. 1979 Jul;22(7):757–759. doi: 10.1021/jm00193a001. [DOI] [PubMed] [Google Scholar]
  12. O'Callaghan C. H., Sykes R. B., Ryan D. M., Foord R. D., Muggleton P. W. Cefuroxime - a new cephalosporin antibiotic. J Antibiot (Tokyo) 1976 Jan;29(1):29–37. doi: 10.7164/antibiotics.29.29. [DOI] [PubMed] [Google Scholar]
  13. Onishi H. R., Daoust D. R., Zimmerman S. B., Hendlin D., Stapley E. O. Cefoxitin, a semisynthetic cephamycin antibiotic: resistance to beta-lactamase inactivation. Antimicrob Agents Chemother. 1974 Jan;5(1):38–48. doi: 10.1128/aac.5.1.38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Reading C., Cole M. Clavulanic acid: a beta-lactamase-inhiting beta-lactam from Streptomyces clavuligerus. Antimicrob Agents Chemother. 1977 May;11(5):852–857. doi: 10.1128/aac.11.5.852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Richmond M. H. Factors influencing the antibacterial action of beta-lactam antibiotics. J Antimicrob Chemother. 1978 Jul;4(B):1–14. doi: 10.1093/jac/4.suppl_b.1. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Ross G. W., Chanter K. V., Harris A. M., Kirby S. M., Marshall M. J., O'Callaghan C. H. Comparison of assay techniques for beta-lactamase activity. Anal Biochem. 1973 Jul;54(1):9–16. doi: 10.1016/0003-2697(73)90241-8. [DOI] [PubMed] [Google Scholar]
  18. Sawai T., Mitsuhashi S., Yamagishi S. Drug resistance of enteric bacteria. XIV. Comparison of beta-lactamases in gram-negative rod bacteria resistant to alpha-aminobenzylpenicillin. Jpn J Microbiol. 1968 Dec;12(4):423–434. doi: 10.1111/j.1348-0421.1968.tb00415.x. [DOI] [PubMed] [Google Scholar]
  19. Sawai T., Yamagishi S., Mitsuhashi S. Penicillinases of Klebsiella pneumoniae and their phylogenetic relationship to penicillinases mediated by R factors. J Bacteriol. 1973 Sep;115(3):1045–1054. doi: 10.1128/jb.115.3.1045-1054.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Stapley E. O., Jackson M., Hernandez S., Zimmerman S. B., Currie S. A., Mochales S., Mata J. M., Woodruff H. B., Hendlin D. Cephamycins, a new family of beta-lactam antibiotics. I. Production by actinomycetes, including Streptomyces lactamdurans sp. n. Antimicrob Agents Chemother. 1972 Sep;2(3):122–131. doi: 10.1128/aac.2.3.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sykes R. B., Matthew M. The beta-lactamases of gram-negative bacteria and their role in resistance to beta-lactam antibiotics. J Antimicrob Chemother. 1976 Jun;2(2):115–157. doi: 10.1093/jac/2.2.115. [DOI] [PubMed] [Google Scholar]
  22. Yamagishi S., O'Hara K., Sawai T., Mitsuhashi S. The purification and properties of penicillin beta-lactamases mediated by transmissible R factors in Escherichia coli. J Biochem. 1969 Jul;66(1):11–20. doi: 10.1093/oxfordjournals.jbchem.a129111. [DOI] [PubMed] [Google Scholar]
  23. Yoshida T., Matsuura S., Mayama M., Kameda Y., Kuwahara S. Moxalactam (6059-S), a novel 1-oxa-beta-lactam with an expanded antibacterial spectrum: laboratory evaluation. Antimicrob Agents Chemother. 1980 Mar;17(3):302–312. doi: 10.1128/aac.17.3.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yoshida T. Structural requirements for antibacterial activity and beta-lactamase stability of 7 beta-arylmalonylamino-7 alpha-methoxy-1-oxacephems. Philos Trans R Soc Lond B Biol Sci. 1980 May 16;289(1036):231–237. doi: 10.1098/rstb.1980.0041. [DOI] [PubMed] [Google Scholar]

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