December 2007 - The Indian Society for Parasitology

Chemotherapy of human trichomoniasis83and growth. Arginine, threonine and leucine constitutethe major amino acids used in energy production.Aminotransferases, e.g., aspartate/aromatic aminoacid:2-oxoglutarate aminotransferase have beenfound to be involved in amino acid metabolism, butmore studies are needed to elucidate their role(s)(Rowe and Lowe, 1986).T. vaginalis utilizes salvage pathways to synthesizepurines and pyrimidines. Nucleoside phosphorylasesand kinases are involved in purine salvage, whereasphosphoribosyltransferases and nucleoside kinasesare involved in pyrimidine synthesis (Zang et al.,2005). T. vaginalis contains two separate nucleotidetransport carriers. One carrier is believed to have highaffinity for adenosine and pyrimidine nucleosides,whereas the other carrier has a site for guanosine anduridine (Harris et al., 1988).NOHNMetronidazoleNO 2O O NO 2SNTinidazoleFig. 4. Chemical structures of 5-nitroimidazoles currentlyapproved for the treatment of human trichomoniasis.CHEMOTHERAPY: CURRENT STATUSFive-nitroimidazoles: 5-nitroimidazoles are theonly approved drugs for the treatment of humantrichomoniasis (Fig. 4). Last review on this topicwas published in the year 2004 (Cudmore et al.,2004). Since then, a lot of research efforts havebeen made in this area, and a critical review ofthe relevant findings is presented here.Metronidazole: Metronidazole (MTZ), a heterocycliccompound with a nitro groupon the fifth position of animidazole ring, was approved in early 1960s for thetreatment of trichomoniasis. It was developed fromthe Streptomyces antibiotic, azomycin (Cudmore etal., 2004). MTZ is also active against a variety ofanaerobic pathogens: both gram-positive and gramnegativebacteria, and protozoans like Entamoebahistolytica and Giardia lamblia. Preparations of MTZare available for oral, intravenous, intravaginal andtopical administration. The drug is usually absorbedcompletely and promptly after oral intake. ItNpenetrates well into body tissues and fluids, includingvaginal secretions, seminal fluid, saliva and breastmilk. Vaginal drug concentration is approximately50% of that in serum. The plasma half-life of MTZ isabout 8.7 h, compared to approximately 12 h for itshydroxy metabolite (Cudmore et al., 2004; Lyons andCarlton, 2004). MTZ is a prodrug. It itself is inactive,but on anaerobic reduction results in the formation of anitro radical. This radical anion acts on nucleic acidDNA strands and disrupts them. Abstraction of atomsof the nucleic acid backbone by the nitro radical,initiates DNA degradation. Finally, cell death occurs.The redox potential of MTZ acts as a driving force fornitro radical formation in anaerobic cells and,therefore, it possesses selective toxicity againstanaerobes (Meri et al., 2000). The nitro radical seemsto act on thymine and adenine residues of DNA andbecause the genome of T. vaginalis is rich in A+Tcontent and, therefore, MTZ shows specificity to thisparasite (Cudmore et al., 2004). Activation of MTZoccurs in an organellar compartment, thehydrogenosome. Hydrogenosomes are the centers forfermentative decarboxylation of pyruvate. Thispathway is linked to substrate-level phosphorylationfor the production of ATP (Kulda, 1999). The keyenzyme is pyruvate:ferredoxin oxidoreductase(PFOR). The electrons released in this reaction aretaken up by ferredoxin. Ferredoxin is a Fe-S protein.The final products are acetate and hydrogen. MTZcompetes for electrons with hydrogenase due to itslower redox potential and consequently, drugactivation occurs (Fig. 5). Small molecules, like MTZ,approach the redox centre more closely in thetrichomonal protein. This results in faster electrontransfer reactions (Vidakovic et al., 2003). Analternative pathway of MTZ activation is also found inthe hydrogenosomes. In this, the source of electrons ismalate instead of pyruvate. Malate is oxidativelydecarboxylated to pyruvate and CO2by a NADdependentmalic enzyme (Hrdy et al., 2005). MTZ isthe drug of choice for the treatment of trichomoniasis.PFORPyruvate Acetyl CoA + CO 2 + e- MTZAcetate [2 Fe-2S] NO 2_HYDROGENOSOMEH 2 DNA damageFig. 5. Diagrammatic representation of molecular mechanismof trichomonacidal action of MTZ.