December 2007 - The Indian Society for Parasitology

Chemotherapy of human trichomoniasis85been suggested that drug-resistance is a multistep ferredoxin-gene expression and thereby, loweredprocess. The aerobic type of resistance appears at the reductive activation of MTZ (Rasoloson et al., 2002).first stage, followed by development of anaerobic type Selection of aerobic-resistant strain of T. vaginalis canof resistance, which is accompanied by a gradual loss be done in vitro by cultivation of trichomonads atof hydrogenosomal proteins involved in drug sublethal concentrations of MTZ for approximatelyactivation pathways (Rasoloson et al., 2002).two months, and it has been demonstrated that MLC ofMTZ increases with increase in O2concentrationAerobic resistance: Selection of strains which(Tachezy et al., 1993).manifest aerobic resistance occurs in the presence ofoxygen. It is important from clinical point of view, as it Anaerobic resistance: Although clinically resistantis commonly present in isolates from treatment- isolates of T. vaginalis usually possess aerobicrefractory patients. Impaired oxygen-scavenging resistance, but anaerobically resistant strains havepathways appear to be responsible for aerobic also been isolated. In vitro, it takes more than one yearresistance. Increased levels of intracellular oxygen to select an anaerobically-resistant strain byinterfere with drug activation (Rasoloson et al., 2001). cultivating trichomonads at gradually increasingDecreased hydrogenase activity and thereby, decrease drug-pressure. Such strains are able to toleratein hydrogen production is responsible for impaired extremely high concentrations of MTZ (Kulda et al.,oxygen scavenging. Also, decreased oxidase activity 1993). Drug activating pathways in themight be responsible for increased O2concentration in hydrogenosomes are usually decreased or absent inthe hydrogenosome (Upcroft and Upcroft, 2001). Due this type of resistance. The loss of pyruvate:ferredoxinto electronegative nature of oxygen atoms, they oxidoreductase (PFOR) activity is important. Otherscompete with MTZ for ferredoxin-bound electrons, include decrease in ferredoxin, malic enzyme andresulting in impaired reduction and hence, generation NAD:ferredoxin oxidoreductase levels (Kulda,of active form of MTZ. Also, in the presence of 1999). Instead, 2-oxoacid oxidoreductases activityoxygen, reoxidation of reduced nitro radicals occurs. appears to increase. This alternate pathway does notThis step is known as futile cycling (Cudmore et al., donate electrons to ferredoxin and, therefore, results2004). Alternatively, decreased ferredoxin levels have in the circumvention of the activation of MTZbeen found in aerobically-resistant strains. The (Upcroft and Upcroft, 2001). Also, it has beendefective redox properties of ferredoxin may be proposed that to acquire high level of drug-resistance,contributed to reduced transcription of ferredoxin both pyruvate- and malate-dependent pathways ofgene due to a point-mutation in the 5’ region. This MTZ activation are eliminated from themutation results in reduced binding affinity for a 23- hydrogenosomes of trichomonads (Hrdy et al., 2005).kDa transcriptional protein. This results in reducedOTHER CHEMOTHERAPEUTIC AGENTSResistanceA number of studies have been published, whichdemonstrate the in vitro and in vivo trichomonicidalactivities of non-imidazole drugs.AerobicPoint-mutationDecreased expressionof ferredoxin geneAnaerobicDecreasedPFORactivityHamycin: It is an aromatic polyene related toamphotericin B. Studies have shown that hamycin atlow concentrations kills both MTZ-sensitive and -resistant strains of T. vaginalis (Lushbaugh et al.,1995). The drug is currently in use in Indiaas a topicaltreatment for trichomoniasis. Unfortunately, reportedside effects in patients indicate that the toxicity ofhamycin may limit future clinical applications(Cudmore et al., 2004).Loweredactivation ofMTZFig. 7. Mechanisms of drug-resistance in T. vaginalis.P a r o m o m y c i n ( a m i n o s i d i n e ) : I t i s a naminoglycoside used as an oral agent to treat E.histolytica infection, cryptosporidiosis and giardiasis.Paromomycin formulated as a 6.25% cream has beenused to treat trichomoniasis in patients who had failed