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. 1984 Nov;26(5):665–669. doi: 10.1128/aac.26.5.665

Ferredoxin-linked reduction of metronidazole in Clostridium pasteurianum.

D L Lockerby, H R Rabin, L E Bryan, E J Laishley
PMCID: PMC179990  PMID: 6517554

Abstract

Clostridium pasteurianum cell-free extracts enzymatically reduced metronidazole when coupled by hydrogenase via reduced ferredoxin. A 5 mM concentration of methyl viologen, flavin adenine dinucleotide, or flavin mononucleotide could completely replace ferredoxin (0.05 mM) in the in vitro reduction assay system, whereas 5 mM benzyl viologen was less effective. However, when these electron carriers were used at a concentration of 0.05 mM, there was a drastic loss in their abilities to couple the metronidazole reduction system compared with the comparable concentration of ferredoxin. It is not understood why these flavin coenzymes participate in this enzymatic reaction. NAD and NADP had no activity when substituted for ferredoxin in the enzyme system. Two reduced ferredoxin-linked pathways, "metronidazole reductase" and the inducible dissimilatory sulfite reductase system, when combined in a single in vitro competition experiment demonstrated a preferential flow of electrons to metronidazole away from sulfite. A proposed bactericidal mechanism for metronidazole against C. pasteurianum incorporating the above findings is discussed.

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Selected References

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

  1. Edwards D. I., Dye M., Carne H. The selective toxicity of antimicrobial nitroheterocyclic drugs. J Gen Microbiol. 1973 May;76(1):135–145. doi: 10.1099/00221287-76-1-135. [DOI] [PubMed] [Google Scholar]
  2. Edwards D. I. Mechanisms of selective toxicity of metronidazole and other nitroimidazole drugs. Br J Vener Dis. 1980 Oct;56(5):285–290. doi: 10.1136/sti.56.5.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Edwards D. I. The action of metronidazole on DNA. J Antimicrob Chemother. 1977 Jan;3(1):43–48. doi: 10.1093/jac/3.1.43. [DOI] [PubMed] [Google Scholar]
  4. Goldman P. The development of 5-nitroimidazoles for the treatment and prophylaxis of anaerobic bacterial infections. J Antimicrob Chemother. 1982 Aug;10 (Suppl A):23–33. doi: 10.1093/jac/10.suppl_a.23. [DOI] [PubMed] [Google Scholar]
  5. Harrison G. I., Laishley E. J., Krouse H. R. Stable isotope fractionation by Clostridium pasteurianum. 3. Effect of SeO32- on the physiology and associated sulfur isotope fractionation during SO32- and SO42- reductions. Can J Microbiol. 1980 Aug;26(8):952–958. doi: 10.1139/m80-162. [DOI] [PubMed] [Google Scholar]
  6. Harrison G. I., Laishley E. J., Krouse H. R. Stable isotope fractionation by Clostridium pasteurianum. 4. Sulfur isotope fractionation during enzymatic S3O6(2-), S2O3(2-), and SO3(2-) reductions. Can J Microbiol. 1981 Aug;27(8):824–834. doi: 10.1139/m81-127. [DOI] [PubMed] [Google Scholar]
  7. Harrison G., Curle C., Laishley E. J. Purification and characterization of an inducible dissimilatory type sulfite reductase from Clostridium pasteurianum. Arch Microbiol. 1984 May;138(1):72–78. doi: 10.1007/BF00425411. [DOI] [PubMed] [Google Scholar]
  8. Laishley E. J., Krouse H. R. Stable isotope fractionation by Clostridium pasteurianum. 2. Regulation of sulfite reductases by sulfur amino acids and their influence on sulfur isotope fractionation during SO32- and SO42- reduction. Can J Microbiol. 1978 Jun;24(6):716–724. doi: 10.1139/m78-120. [DOI] [PubMed] [Google Scholar]
  9. Laishley E. J., Lin P. M., Peck H. D., Jr A ferredoxin-linked sulfite reductase from Clostridium pasteurianum. Can J Microbiol. 1971 Jul;17(7):889–895. doi: 10.1139/m71-142. [DOI] [PubMed] [Google Scholar]
  10. Lindmark D. G., Müller M. Antitrichomonad action, mutagenicity, and reduction of metronidazole and other nitroimidazoles. Antimicrob Agents Chemother. 1976 Sep;10(3):476–482. doi: 10.1128/aac.10.3.476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. MORTENSON L. E., VALENTINE R. C., CARNAHAN J. E. An electron transport factor from Clostridium pasteurianum. Biochem Biophys Res Commun. 1962 Jun 4;7:448–452. doi: 10.1016/0006-291x(62)90333-9. [DOI] [PubMed] [Google Scholar]
  12. Müller M., Lindmark D. G. Uptake of metronidazole and its effect on viability in trichomonads and Entamoeba invadens under anaerobic and aerobic conditions. Antimicrob Agents Chemother. 1976 Apr;9(4):696–700. doi: 10.1128/aac.9.4.696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Müller M. Mode of action of metronidazole on anaerobic bacteria and protozoa. Surgery. 1983 Jan;93(1 Pt 2):165–171. [PubMed] [Google Scholar]
  14. Peterson F. J., Mason R. P., Hovsepian J., Holtzman J. L. Oxygen-sensitive and -insensitive nitroreduction by Escherichia coli and rat hepatic microsomes. J Biol Chem. 1979 May 25;254(10):4009–4014. [PubMed] [Google Scholar]
  15. Reynolds A. V. The activity of nitro-compounds against Bacteroides fragilis is related to their electron affinity. J Antimicrob Chemother. 1981 Aug;8(2):91–99. doi: 10.1093/jac/8.2.91. [DOI] [PubMed] [Google Scholar]
  16. Tally F. P., Goldin B. R., Sullivan N., Johnston J., Gorbach S. L. Antimicrobial activity of metronidazole in anaerobic bacteria. Antimicrob Agents Chemother. 1978 Mar;13(3):460–465. doi: 10.1128/aac.13.3.460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Yoch D. C., Carithers R. P. Bacterial iron-sulfur proteins. Microbiol Rev. 1979 Sep;43(3):384–421. doi: 10.1128/mr.43.3.384-421.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]

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