Metronidazole and related 5-nitroimidazoles are the only available drugs in the treatment of human urogenital trichomoniasis caused by the protozoan parasite Trichomonas vaginalis. The drugs are activated to cytotoxic anion radicals by their reduction within the hydrogenosomes. It has been established that electrons required for metronidazole activation are released from pyruvate by the activity of pyruvate:ferredoxin oxidoreductase and transferred to the drug by a low-redox-potential carrier, ferredoxin. Here we describe a novel pathway involved in the drug activation within the hydrogenosome. The source of electrons is malate, another major hydrogenosomal substrate, which is oxidatively decarboxylated to pyruvate and CO2 by NAD-dependent malic enzyme. The electrons released during this reaction are transferred from NADH to ferredoxin by NADH dehydrogenase homologous to the catalytic module of mitochondrial complex I, which uses ferredoxin as electron acceptor. Trichomonads acquire high-level metronidazole resistance only after both pyruvate- and malate-dependent pathways of metronidazole activation are eliminated from the hydrogenosomes.

Department of Parasitology Charles University Prague Vinicná 7 128 44 Prague 2 Czech Republic

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Cerkasovova, A., J. Cerkasov, and J. Kulda. 1984. Metabolic differences between metronidazole resistant and susceptible strains of Tritrichomonas foetus. Mol. Biochem. Parasitol. 11:105-118. PubMed

Chapman, A., R. Cammack, D. Linstead, and D. Lloyd. 1985. The generation of metronidazole radicals in hydrogenosomes isolated from Trichomonas vaginalis. J. Gen. Microbiol. 131:2141-2144. PubMed

Clark, C. G., and L. S. Diamond. 2002. Methods for cultivation of luminal parasitic protists of clinical importance. Clin. Microbiol. Rev. 15:329-341. PubMed PMC

Drmota, T., P. Proost, R. M. Van, F. Weyda, J. Kulda, and J. Tachezy. 1996. Iron-ascorbate cleavable malic enzyme from hydrogenosomes of Trichomonas vaginalis: purification and characterization. Mol. Biochem. Parasitol. 83:221-234. PubMed

Edwards, D. I. 1993. Nitroimidazole drugs—action and resistance mechanisms. II. Mechanisms of resistance. J. Antimicrob. Chemother. 31:201-210. PubMed

Hrdy, I., R. P. Hirt, P. Dolezal, L. Bardonova, P. G. Foster, J. Tachezy, and T. M. Embley. 2004. Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I. Nature 432:618-622. PubMed

Kulda, J. 1999. Trichomonads, hydrogenosomes and drug resistance. Int. J. Parasitol. 29:199-212. PubMed

Kulda, J., J. Tachezy, and A. Cerkasovova. 1993. In vitro induced anaerobic resistance to metronidazole in Trichomonas vaginalis. J. Eukaryot. Microbiol. 40:262-269. PubMed

Kulda, J., M. Vojtechovska, J. Tachezy, P. Demes, and E. Kunzova. 1982. Metronidazole resistance of Trichomonas vaginalis as a cause of treatment failure in trichomoniasis—a case report. Br. J. Vener. Dis. 58:394-399. PubMed PMC

Land, K. M., M. G. Gadillo-Correa, J. Tachezy, S. Vanacova, C. L. Hsieh, R. Sutak, and P. J. Johnson. 2004. Targeted gene replacement of a ferredoxin gene in Trichomonas vaginalis does not lead to metronidazole resistance. Mol. Microbiol. 51:115-122. PubMed

Lindmark, D. G., and M. Muller. 1976. Antitrichomonad action, mutagenicity, and reduction of metronidazole and other nitroimidazoles. Antimicrob. Agents Chemother. 10:476-482. PubMed PMC

Marczak, R., T. E. Gorrell, and M. Muller. 1983. Hydrogenosomal ferredoxin of the anaerobic protozoon, Tritrichomonas foetus. J. Biol. Chem. 258:12427-12433. PubMed

Moreno, S. N., R. P. Mason, and R. Docampo. 1984. Distinct reduction of nitrofurans and metronidazole to free radical metabolites by Tritrichomonas foetus hydrogenosomal and cytosolic enzymes. J. Biol. Chem. 259:8252-8259. PubMed

Muller, M. 1986. Reductive activation of nitroimidazoles in anaerobic microorganisms. Biochem. Pharmacol. 35:37-41. PubMed

Muller, M. 1993. The hydrogenosome. J. Gen. Microbiol. 139:2879-2889. PubMed

Quon, D. V., C. E. d'Oliveira, and P. J. Johnson. 1992. Reduced transcription of the ferredoxin gene in metronidazole-resistant Trichomonas vaginalis. Proc. Natl. Acad. Sci. USA 89:4402-4406. PubMed PMC

Rasoloson, D., S. Vanacova, E. Tomkova, J. Razga, I. Hrdy, J. Tachezy, and J. Kulda. 2002. Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis. Microbiology 148:2467-2477. PubMed

Steinbuchel, A., and M. Muller. 1986. Anaerobic pyruvate metabolism of Tritrichomonas foetus and Trichomonas vaginalis hydrogenosomes. Mol. Biochem. Parasitol. 20:57-65. PubMed

Sutak, R., P. Dolezal, H. L. Fiumera, I. Hrdy, A. Dancis, M. Gadillo-Correa, P. J. Johnson, M. Muller, and J. Tachezy. 2004. Mitochondrial-type assembly of FeS centers in the hydrogenosomes of the amitochondriate eukaryote Trichomonas vaginalis. Proc. Natl. Acad. Sci. USA 101:10368-10373. PubMed PMC

Thong, K. W., and G. H. Coombs. 1987. Comparative study of ferredoxin-linked and oxygen-metabolizing enzymes of trichomonads. Comp. Biochem. Physiol. B 87:637-641. PubMed

Vidakovic, M., C. R. Crossnoe, C. Neidre, K. Kim, K. L. Krause, and J. P. Germanas. 2003. Reactivity of reduced [2Fe-2S] ferredoxins parallels host susceptibility to nitroimidazoles. Antimicrob. Agents Chemother. 47:302-308. PubMed PMC

Novel functions of an iron-sulfur flavoprotein from Trichomonas vaginalis hydrogenosomes

Flavodiiron protein from Trichomonas vaginalis hydrogenosomes: the terminal oxygen reductase