Skip to main content

Hydrogenosome: The Site of 5-Nitroimidazole Activation and Resistance

  • Chapter
  • First Online:
Hydrogenosomes and Mitosomes: Mitochondria of Anaerobic Eukaryotes

Part of the book series: Microbiology Monographs ((MICROMONO,volume 9))

Abstract

Derivatives of 5-nitroimidazole, such as metronidazole or tinidazole, are the drugs of choice for treatment of sexually transmitted infections of humans caused by the parasitic protist Trichomonas vaginalis. These drugs with selective activity against anaerobic and microaerophilic microorganisms enter the trichomonad cell and accumulate in hydrogenosomes, where their antimicrobial properties are activated. In this chapter we discuss metabolic pathways of hydrogenosomes involved in metronidazole activation. We also summarize present knowledge on the development and biochemical mechanisms of metronidazole resistance in T. vaginalis and the related cattle parasite Tritrichomonas foetus. Implications of data from the T. vaginalis genome project suggesting the presence of novel mechanisms of drug resistance are also considered.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Brown DM, Upcroft JA, Dodd HN, Chen N, Upcroft P (1999) Alternative 2-keto acid oxidoreductase activities in Trichomonas vaginalis. Mol Biochem Parasitol 98:203–214

    Article  PubMed  CAS  Google Scholar 

  • Carlier JP, Sellier N, Rager MN, Reysset G (1997) Metabolism of a 5-nitroimidazole in susceptible and resistant isogenic strain of Bacterioides fragilis. Antimicrob Agents Chemother 41:1495–1499

    PubMed  CAS  Google Scholar 

  • Carlton JM, Hirt RP, Silva JC, Delcher AL, Schatz M, Zhao Q, Wortman JR, Bidwell SL, Alsmark UCM, Besteiro S, Sicheritz-Ponten T, Noel CJ, Dacks JB, Foster PG, Simillion C, Van de Peer Y, Miranda-Saavedra D, Barton GJ, Westrop GD, Muller S, Dessi D, Fiori PL, Ren QH, Paulsen I, Zhang HB, Bastida-Corcuera FD, Simoes-Barbosa A, Brown MT, Hayes RD, Mukherjee M, Okumura CY, Schneider R, Smith AJ, Vanacova S, Villalvazo M, Haas BJ, Pertea M, Feldblyum TV, Utterback TR, Shu CL, Osoegawa K, Jong PJD, Hrdý I, Horvathova L, Zubacova Z, Horvathova L, Malik SB, Logsdon JM, Henze K, Gupta A, Wang CC, Dunne RL, Upcroft JA, Upcroft P, White O, Salzberg SL, Tang P, Chiu CH, Lee YS, Embley TM, Coombs GH, Mottram JC, Tachezy J, Fraser-Liggett CM, Johnson PJ (2007) Draft genome sequence of the sexually transmitted pathogen Trichomonas vaginalis. Science 315:207–212

    Article  PubMed  Google Scholar 

  • Čerkasov J, Čerkasovová A, Kulda J, Vilhelmová D (1978) Respiration of hydrogenosomes of Tritrichomonas foetus. J Biol Chem 253:1207–1214

    PubMed  Google Scholar 

  • Čerkasovová A, Čerkasov J, Kulda J (1984) Metabolic differences between metronidazole resistant and susceptible strains of Tritrichomonas foetus. Mol Biochem Parasitol 11:105–118

    Article  PubMed  Google Scholar 

  • Čerkasovová A, Novák J, Čerkasov J, Kulda J, Tachezy J (1988) Metabolic properties of Trichomonas vaginalis resistant to metronidazole under anaerobic conditions. Acta Univ Carol Biol 30:505–512

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cudmore S, Delgaty KL, Hayward-McClelland SF, Petrin DP, Garber E (2004) Treatment of infections caused by metronidazole-resistant Trichomonas vaginalis. Clin Microbiol Rev 17:783–793

    Article  PubMed  CAS  Google Scholar 

  • Docampo R, Moreno SN, Mason RP (1987) Free radical intermediates in the reaction of pyruvate : ferredoxin oxidoreductase in Tritrichomonas foetus hydrogenosomes. J Biol Chem 262:12417–12420

    PubMed  CAS  Google Scholar 

  • Dunne RL, Dunn LA, Upcroft P, O'Donoghue PJ, Upcroft JA (2003) Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis. Cell Res 132:239–249

    Article  Google Scholar 

  • Edwards DI (1993a) Nitroimidazole drugs action and resistance mechanisms. I. Mechanisms of action. J Antimicrob Chemother 31:9–20

    Article  PubMed  CAS  Google Scholar 

  • Edwards DI (1993b) Nitroimidazole drugs action and resistance mechanisms. II. Mechanisms of resistance. J Antimicrob Chemother 31:201–210

    Article  PubMed  CAS  Google Scholar 

  • Ellis JE, Cole D, Lloyd D (1992) Influence of oxygen on the fermentative metabolism of metronidazole-sensitive and resistant strains of Trichomonas vaginalis. Mol Biochem Parasitol 56:79–88

    Article  PubMed  CAS  Google Scholar 

  • Ellis JE, Yarlett N, Cole D, Humphreys MJ, Lloyd D (1994) Antioxidant defenses in the microaerophilic protozoan Trichomonas vaginalis—comparison of metronidazole-resistant and sensitive strains. Microbiol-SGM 140:2489–2494

    Article  CAS  Google Scholar 

  • Haggoud A, Reysset G, Azeddoug H, Sebald M (1994) Nucleotide sequence analysis of two 5-nitroimidazole resistance determinants from Bacterioides strains and of a new insertion sequence upstream of the two genes. Antimicrob Agents Chemother 38:1047–1051

    PubMed  CAS  Google Scholar 

  • Hrdý I, Mertens E, Van Schaftingen E (1993) Identification, purification and separation of different isozymes of NADP-specific malic enzyme from Tritrichomonas foetus. Mol Biochem Parasitol 57:253–260

    Article  PubMed  Google Scholar 

  • Hrdý I, Hirt RP, Doležal P, Bardoňová L, Foster PG, Tachezy J, Embley TM (2004) Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I. Nature 432:618–622

    Article  PubMed  CAS  Google Scholar 

  • Hrdý I, Cammack R, Kulda J, Tachezy J (2005) Alternative pathway of metronidazole activation in Trichomonas vaginalis hydrogenosomes. Antimicrob Agents Chemother 49:5033–5036

    Article  PubMed  CAS  Google Scholar 

  • Hrdý I, Tachezy J, Müller M (2007) Metabolism if trichomonad hydrogenosomes, in this volume. Springer, Heidelberg

    Google Scholar 

  • Kabíčková H, Kulda J, Čerkasovová A, Němcová H (1988) Metronidazole resistant Tritrichomonas foetus: activities of hydrogenosomal enzymes in course of development of anaerobic resistance. Acta Univ Carol Biol 30:513–519

    Google Scholar 

  • Kulda J (1999) Trichomonads, hydrogenosomes and drug resistance. Int J Parasitol 29:199–212

    Article  PubMed  CAS  Google Scholar 

  • Kulda J, Čerkasov J, Demeš P, Čerkasovová A (1984) Tritrichomonas foetus: stable anaerobic resistance to metronidazole in vitro. Exp Parasitol 57:93–103

    Article  PubMed  CAS  Google Scholar 

  • Kulda J, Kabíčková H, Tachezy J, Čerkasovová A, Čerkasov J (1989) Metronidazole resistant trichomonads: mechanisms of in vitro developed anaerobic resistance. In: Lloyd D, Coombs GH, Paget TAP (eds) Biochemistry and molecular biology of anaerobic protozoa. Harwood, London, pp 137–160

    Google Scholar 

  • Kulda J, Tachezy J, Čerkasovová A (1993) In vitro induced anaerobic resistance to metronidazole in Trichomonas vaginalis. J Eukaryot Microbiol 40:262–269

    Article  PubMed  CAS  Google Scholar 

  • Land KM, Clemens DL, Johnson PJ (2001) Loss of multiple hydrogenosomal proteins associated with organelle metabolism and high-level drug resistance in trichomonads. Exp Parasitol 97:102–110

    Article  PubMed  CAS  Google Scholar 

  • Land KM, Delgadillo-Correa MG, Tachezy J, Vaňáčová S, Hsieh CL, Šut'ák R, Johnson PJ (2004) Targeted gene replacement of a ferredoxin gene in Trichomonas vaginalis does not lead to metronidazole resistance. Mol Microbiol 51:115–122

    Article  PubMed  CAS  Google Scholar 

  • Leiros HKS, Kozielski-Stuhrmann S, Kapp U, Terradot L, Leonard GA, McSweeney SM (2004) Structural basis of 5-nitroimidazole antibiotic resistance. J Biol Chem 279:55840–55849

    Article  PubMed  CAS  Google Scholar 

  • Lindmark DG, Müller M (1973) Hydrogenosome, a cytoplasmic organelle of the anaerobic flagellate Tritrichomonas foetus, and its role in pyruvate metabolism. J Biol Chem 248:7724–7728

    PubMed  CAS  Google Scholar 

  • Lloyd D, Kristensen B (1985) Metronidazole inhibition of hydrogen production in vivo in drug-sensitive and resistant strains of Trichomonas vaginalis. J Gen Microbiol 131:849–853

    PubMed  CAS  Google Scholar 

  • Lloyd D, Pedersen JZ (1985) Metronidazole anion radical anion generation in vivo in Trichomonas vaginalis: oxygen quenching is enhanced in a drug-resistant strain. J Gen Microbiol 131:87–92

    PubMed  CAS  Google Scholar 

  • Lossick JG, Müller M, Gorrell TE (1986) In vitro drug susceptibility and doses of metronidazole required for cure in cases of refractory vaginal trichomoniasis. J Infect Dis 153:948–955

    PubMed  CAS  Google Scholar 

  • Meingassner JG, Mieth H (1976) Cross-resistance of trichomonads to 5-nitroimidazole derivatives. Experientia 32:183–184

    Article  PubMed  CAS  Google Scholar 

  • Meingassner JG, Thurner J (1979) Strain of Trichomonas vaginalis resistant to metronidazole and other 5-nitroimidazoles. Antimicrob Agents Chemother 15:254–257

    PubMed  CAS  Google Scholar 

  • Meingassner JG, Mieth H, Czok R, Lindmark DG, Müller M (1978) Assay conditions and the demonstration of nitroimidazole resistance in Tritrichomonas foetus. Antimicrob Agents Chemother 13:1–3

    PubMed  CAS  Google Scholar 

  • Mendz GL, Mégraud F (2002) Is the molecular basis of metronidazole resistance in microaerophilic organisms understood? Trends Microbiol 10:370–375

    Article  PubMed  CAS  Google Scholar 

  • Meri T, Jokiranta TS, Suhonen L, Meri S (2000) Resistance of Trichomonas vaginalis to metronidazole: report of the first three cases from Finland and optimization of in vitro susceptibility testing under various oxygen concentrations. J Clin Microbiol 38:763–767

    PubMed  CAS  Google Scholar 

  • Moreno SN, Mason RP, Muniz RP, Cruz FS, Docampo R (1983) Generation of free radicals from metronidazole and other nitroimidazoles by Tritrichomonas foetus. J Biol Chem 258:4051–4054

    PubMed  CAS  Google Scholar 

  • Moreno SN, Mason RP, Docampo R (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  CAS  Google Scholar 

  • Müller M (1973) Biochemical cytology of trichomonad flagellates. I. Subcellular localization of hydrolases, dehydrogenases, and catalase in Tritrichomonas foetus. J Cell Biol 57:453–474

    Article  PubMed  Google Scholar 

  • Müller M, Gorrell T (1983) Metabolism and metronidazole uptake in Trichomonas vaginalis isolates with different metronidazole susceptibilities. Antimicrob Agents Chemother 24:667–673

    PubMed  Google Scholar 

  • Müller M, Lindmark DG (1976) Uptake of metronidazole and its effect on viability in trichomonads and Entamoeba invadens under anaerobic and aerobic conditions. Antimicrob Agents Chemother 9:696–700

    PubMed  Google Scholar 

  • Müller M, Lossick JG, Gorrell TE (1988) In vitro susceptibility of Trichomonas vaginalis to metronidazole and treatment outcome in vaginal trichomoniasis. Sex Transm Dis 15:17–24

    Article  PubMed  Google Scholar 

  • Quon DV, d'Oliveira CE, Johnson PJ (1992) Reduced transcription of the ferredoxin gene in metronidazole-resistant Trichomonas vaginalis. Proc Natl Acad Sci USA 89:4402–4406

    Article  PubMed  CAS  Google Scholar 

  • Rasoloson D, Tomková E, Cammack R, Kulda J, Tachezy J (2001) Metronidazole-resistant strains of Trichomonas vaginalis display increased susceptibility to oxygen. Parasitology 123:45–56

    Article  PubMed  CAS  Google Scholar 

  • Rasoloson D, Vaňáčová S, Tomková E, Rázga J, Hrdý I, Tachezy J, Kulda J (2002) Mechanisms of in vitro development of resistance to metronidazole in Trichomonas vaginalis. Microbiol-SGM 148:2467–2477

    CAS  Google Scholar 

  • Samarawickrema NA, Brown DM, Upcroft JA, Thammapalerd N, Upcroft P (1997) Involvement of superoxide dismutase and pyruvate : ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica. J Antimicrob Chemother 40:833–840

    Article  PubMed  CAS  Google Scholar 

  • Saraiva LM, Vicente JB, Teixeira M (2004) The role of the flavodiiron proteins in microbial nitric oxide detoxification. Adv Microb Physiol 49:77–129

    Article  PubMed  CAS  Google Scholar 

  • Sobel JD, Nagappan V, Nyirjesi P (1999) Metronidazole resistant vaginal trichomoniasis—an emerging problem. N Engl J Med 341:292

    Article  PubMed  CAS  Google Scholar 

  • Tachezy J, Kulda J, Tomková E (1993) Aerobic resistance of Trichomonas vaginalis to metronidazole induced in vitro. Parasitology 106:31–37

    Article  PubMed  CAS  Google Scholar 

  • Upcroft P, Upcroft JA (2001) Drug targets and mechanisms of resistance in the anaerobic protozoa. Clin Microbiol Rev 14:150–164

    Article  PubMed  CAS  Google Scholar 

  • Upcroft JA, Campbell RW, Benakli K, Upcroft P, Vanelle P (1999) Efficacy of new 5-nitroimidazoles against metronidazole-susceptible and -resistant Giardia, Trichomonas and Entamoeba spp. Antimicrob Agents Chemother 43:73–76

    PubMed  CAS  Google Scholar 

  • Wagner G, Levin R (1978) Oxygen tension of the vaginal surface during sexual stimulation in humans. Fertil Steril 30:50–53

    PubMed  CAS  Google Scholar 

  • Wassman C, Hellberg A, Tannich E, Bruchhaus I (1999) Metronidazole resistance in protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. J Biol Chem 274:26051–26056

    Article  Google Scholar 

  • Yarlett N, Yarlett NC, Lloyd D (1986a) Metronidazole resistant clinical isolates of Trichomonas vaginalis have lowered oxygen affinities. Mol Biochem Parasitol 19:111–116

    Article  PubMed  CAS  Google Scholar 

  • Yarlett N, Yarlett NC, Lloyd D (1986b) Ferredoxin-dependent reduction of nitroimidazole derivatives in drug-resistant and susceptible strains of Trichomonas vaginalis. Biochem Pharmacol 35:1703–1708

    Article  PubMed  CAS  Google Scholar 

  • Yarlett N, Rowlands CC, Evans JC, Yarloett N, Lloyd D (1987) Nitroimidazole and oxygen radicals detected by electron spin resonance in hydrogenosomal and cytosolic fractions from Trichomonas vaginalis. Mol Biochem Parasitol 24:255–261

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jaroslav Kulda .

Editor information

Jan Tachezy

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Kulda, J., Hrdý, I. (2007). Hydrogenosome: The Site of 5-Nitroimidazole Activation and Resistance. In: Tachezy, J. (eds) Hydrogenosomes and Mitosomes: Mitochondria of Anaerobic Eukaryotes. Microbiology Monographs, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7171_2007_112

Download citation

Publish with us

Policies and ethics