Abstract
Toxoplasma gondii is an apicomplexan parasite that infects and proliferates within many different types of host cells and infects virtually all warm-blooded animals and humans. Trypanosoma brucei is an extracellular kinetoplastid that causes human African trypanosomiasis and Nagana disease in cattle, primarily in rural sub-Saharan Africa. Current treatments against both parasites have limitations, e.g., suboptimal efficacy and adverse side effects. Here, we investigate the potential cellular and molecular targets of a trithiolato-bridged arene ruthenium complex conjugated to 9-(2-hydroxyethyl)-adenine (1), which inhibits both parasites with IC50s below 10−7 M. Proteins that bind to 1 were identified using differential affinity chromatography (DAC) followed by shotgun-mass spectrometry. A trithiolato-bridged ruthenium complex decorated with hypoxanthine (2) and 2-hydroxyethyl-adenine (3) were included as controls. Transmission electron microscopy (TEM) revealed distinct ultrastructural modifications in the mitochondrion induced by (1) but not by (2) and (3) in both species. DAC revealed 128 proteins in T. gondii and 46 proteins in T. brucei specifically binding to 1 but not 2 or 3. In T. gondii, the most abundant was a protein with unknown function annotated as YOU2. This protein is a homolog to the human mitochondrial inner membrane translocase subunit Tim10. In T. brucei, the most abundant proteins binding specifically to 1 were mitochondrial ATP-synthase subunits. Exposure of T. brucei bloodstream forms to 1 resulted in rapid breakdown of the ATP-synthase complex. Moreover, both datasets contained proteins involved in key steps of metabolism and nucleic acid binding proteins.
Highlights
Introduction conditions of the Creative CommonsToxoplasma gondii and Trypanosoma brucei belong to two evolutionary distant eukaryotic phyla, namely the clade Alveolata of the super-group Diaphoretickes in the case of T. gondii, and the group Euglenozoa of super-group Excavata in the case of T. brucei [1]
While toxoplasmosis is a food-borne disease, human African trypanosomiasis (HAT) is a vector-borne disease, and transmission of T. brucei gambiense and T. b. rhodesiense to humans occurs via the tsetse fly [5]
We investigated the activity of compound 1, which was identified in the screening for anti-T. gondii activity, containing a 9-(2-hydroxyethyl)-adenine group, against T. brucei
Summary
Toxoplasma gondii and Trypanosoma brucei belong to two evolutionary distant eukaryotic phyla, namely the clade Alveolata of the super-group Diaphoretickes in the case of T. gondii, and the group Euglenozoa of super-group Excavata in the case of T. brucei [1]. Compounds targeting mitochondrial function and structural integrity represent attractive drug candidates for the treatment of both parasitic infections. Extensive research has been carried out to identify suitable molecular drug targets in protozoan parasites that cause diseases in animals and humans [12,13]. Published in vitro studies have revealed that trithiolato-bridged dinuclear ruthenium(II)–arene complexes were effective against T. gondii [14,15,16,17], Neospora caninum [17,18], and T. brucei [19]. We investigated whether common (sub-)cellular and/or molecular targets exist in these evolutionary and ecologically distant protozoan parasites using electron microscopy of cells treated with all three compounds. Arene complex with 2–thioxanthine as one of the bridge thiols, and 3 is 9–(2–hydroxyethyl) –adenine
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