Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

Abstract

Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

The Mercaptopyruvate Sulfurtransferase of Trichomonas vaginalis Links Cysteine Catabolism to the Production of Thioredoxin Persulfide

“…The infection can be treated effectively with metronidazole and other nitroimidazole drugs such as tinidazole. However, there is growing concern over the incidence and the level of drug resistance, and there is a need for new drugs with a different mode of action (2,8). Sulfur amino acid metabolism is one of a number of areas under investigation with a view to identifying targets for drug development (9 -11).…”

Trichomonas vaginalis: Clinical relevance, pathogenicity and diagnosis

“…These antibiotics from the 5-nitroimidazole family exert their antimicrobial activity by disrupting the redox system of the parasite, with metabolic products of the drug binding to proteins in the thioredoxin mediated redox network and inhibiting thioredoxin reductase (Leitsch et al, 2009). The antimicrobial properties of these drugs rely on reduction at the nitro group, which occurs after passive diffusion of the drug into the hydrogenosome of the cell, generating nitroradical anions, and further reduced reactive intermediates (Dunne et al, 2003).Whilst in bacterial cells these nitroradicals would cause DNA damage, and cell death, the precise mechanism of by which they damage eukaryotic microorganisms is poorly understood (Kulda, 1999).…”

Antiparasitic properties of homoallylamines and related compounds

“…The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole ( Dunne et al 2003) is frequently reported, and crossresistance among the family of 5-nitroimidazole drugs is also common. Moreover, resistant organisms are cosmopolitan in distribution and are of considerable concern as Trichomonas infection are linked to vaginal HIV transmission Kerndt 1998, Lo et al 2002).…”