Antitrichomonad Action, Mutagenicity, and Reduction of Metronidazole and Other Nitroimidazoles

Abstract

Twelve 4- and 5-nitroimidazole derivatives, including metronidazole and two of its metabolites, tinidazole, dimetridazole, and nimorazole, were tested for antitrichomonad action on Tritrichomonas foetus (KV 1 ) and Trichomonas vaginalis (ATCC 30001) for mutagenicity on a nitroreductase-positive (TA 100) and a nitroreductase-deficient (TA 100-FR 1 ) strain of Salmonella typhimurium , as well as for the reducibility of the nitro group by T. foetus homogenates. Compounds with activity <1% of that of metronidazole are regarded as inactive. All antitrichomonad compounds induce mutations and can be reduced. S. typhimurium TA 100 gave mutations under both aerobiosis and anaerobiosis; TA 100-FR 1 , however, gave mutations only under anaerobiosis. Certain compounds that are reducible, and the nonreducible derivatives, were inactive. Metronidazole and its inactive 4-nitro analogue were reduced in a four-electron process in ferredoxin- or methyl viologen-mediated reactions with the same velocity. The results underscore the role of the reduction of the nitro group in the antitrichomonad and in the mutagenic activity of nitroimidazoles.

Metabolic activities of metronidazole-sensitive and -resistant strains of Helicobacter pylori: repression of pyruvate oxidoreductase and expression of isocitrate lyase activity correlate with resistance

“…No further effort was made to optimize the Mtz-based POR assay or to evaluate various exogenous carriers (i.e., ferredoxin or flavodoxin). These results are consistent with numerous studies demonstrating that benzyl viologen is directly reduced by POR, whereas Mtz is indirectly reduced by low-redox carriers such as ferredoxin or flavodoxin (8,28,29). Therefore, the absence of POR activity in Mtz r strains grown in the presence of Mtz cannot be attributed to direct inhibition of POR by Mtz.…”

“…Our study demonstrated that H. pylori possesses a complete and active Krebs cycle. In addition, all of the H. pylori strains examined in this study were found to contain POR and KOR activities, which in anaerobes are the major enzymes responsible for the reduction of nitroimidazole drugs (8,29,31). None of the H. pylori strains examined in this study exhibited NAD-linked pyruvate or ␣-ketoglutarate dehydrogenase activity, commonly found in aerobes and facultative anaerobes.…”

“…However, microaerophiles, like anaerobes, are susceptible to the redox-active 5-nitroimidazole drugs (16,31,54). These drugs, when reduced by low-potential ferredoxins or flavodoxins in a four-electron transfer reaction, form shortlived, DNA-damaging hydroxylamine derivatives (22,26,29,39,54). In the presence of oxygen, oxidation of reduced metronidazole (Mtz) intermediates can generate biologically active superoxide anions (24,39,54).…”

Strain of Trichomonas vaginalis Resistant to Metronidazole and Other 5-Nitroimidazoles

“…The reported similarity in the mechanisms of action of metronidazole, tinidazole, and ninorazole (14) has been confirmed in that showed a markedly decreased susceptibility to all three compounds.…”

Isolation and characterization of Trichomonas vaginalis ferredoxin

“…Metronidazole is a nitroheterocyclic drug that chemically oxidizes reduced ferredoxin (11). In the absence of ferredoxin, metronidazole was reduced at low rates.…”