Abstract
Giardia lamblia (syn. duodenalis, intestinalis) is a globally occurring micro-aerophilic human parasite that causes gastrointestinal disease. Standard treatment of G. lamblia infections is based on the 5-nitroimidazole drugs metronidazole and tinidazole. In two other micro-aerophilic parasites, Entamoeba histolytica and Trichomonas vaginalis, 5-nitroimidazole drugs bind to proteins involved in the thioredoxin-mediated redox network and disrupt the redox equilibrium by inhibiting thioredoxin reductase and depleting intracellular thiol pools. The major aim of this study was to assess whether nitroimidazoles exert a similar toxic effect on G. lamblia physiology.The 5-nitroimidazoles metronidazole and tinidazole were found to bind to the same subset of proteins including thioredoxin reductase. However, in contrast to E. histolytica and T. vaginalis, none of the other proteins bound are candidates for being involved in the thioredoxin-mediated redox network. Translation elongation factor EF-1γ, an essential factor in protein synthesis, was widely degraded upon treatment with 5-nitroimidazoles. 2-Nitroimidazole (azomycin) and the 5-nitroimidazole ronidazole did not bind to any G. lamblia proteins, which is in contrast to previous findings in E. histolytica and T. vaginalis. All nitroimidazoles tested reduced intracellular thiol pools in G. lamblia, but metronidazole, also in contrast to the situation in the other two parasites, had the slightest effect. Taken together, our results suggest that nitroimidazole drugs affect G. lamblia in a fundamentally different way than E. histolytica and T. vaginalis.
Highlights
Giardia lamblia is considered to be the most common protozoan intestinal parasite worldwide (Buret, 2008)
In analogy to our previous work on metronidazole action in E. histolytica (Leitsch et al, 2007) and T. vaginalis (Leitsch et al, 2009), two-dimensional gel electrophoresis (2DE) was performed in order to identify G. lamblia proteins that are bound by metronidazole and other nitroimidazoles (Fig. 1)
Our observations strongly suggest that nitroimidazoles are differently metabolized in G. lamblia as compared to the other two parasites
Summary
Giardia lamblia (syn. duodenalis, intestinalis) is considered to be the most common protozoan intestinal parasite worldwide (Buret, 2008). Duodenalis, intestinalis) is considered to be the most common protozoan intestinal parasite worldwide (Buret, 2008). It causes giardiasis, a disease with symptoms such as diarrhea, nausea and failure to thrive in infected children. Treatment of giardiasis is mainly based on metronidazole (Tejman-Yarden and Eckman, 2011), a 5-nitroimidazole drug which is exclusively toxic to microaerophilic and anaerobic microorganisms (Samuelson, 1999). Another 5-nitroimidazole drug, tinidazole, is often prescribed (Fung and Doan, 2005).
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