Deciphering Mode of Action of JK11 and TG142 Compounds in the Mitochondrion of T. brucei

0488326 - BC 2018 RIV CZ eng O - Others
Váchová, H. - Holzgrabe, U. - Bruhn, H. - Zíková, Alena
Deciphering Mode of Action of JK11 and TG142 Compounds in the Mitochondrion of T. brucei.
2014
R&D Projects: GA MŠMT LL1205
Institutional support: RVO:60077344
Keywords : JK11 * mitochondrion * T. brucei
OECD category: Biochemistry and molecular biology
http://www.parazitologie.cz/protozoologie/Protodny2014/JPD_sbornik_2014.pdf

Causative agents of tropical neglected diseases bring enormous disease burden to the developing countries. Importantly, chemical compounds belonging to 4-oxopiperidine-3,5-dicarboxylates strongly inhibit the in vitro and in vivo growth of medically important parasites such as Trypanosoma brucei, Plasmodium falciparum, Leishmania major and bacteria as Staphylococcus epidermis and Pseudomona aeruginosa. Two compounds affecting the cell viability of the insect procyclic stage (PS) and the bloodstream stage (BS) in uM concentration were chosen for a detailed characterization of their mode of action. Interestingly, the mitochondrial membrane potential (um) of the BF cells is strongly decreased upon the treatment by these chemicals. Since FoF1 ATPase is responsible for maintaining the um, the activity of this complex was tested in vitro. Both compounds decreased the total ATPase activity at similar level as azide and oligomycin, known inhibitors of FoF1 ATPase. Moreover the synthetic activity of this complex was also strongly affected upon the treatment suggesting that these potential chemotherapeutics affects both directions of the FoF1 ATPsynthase/ATPase activity. In vitro activity of the purified F1ATPase was unchanged upon the treatment implying that these drugs may act only on fully assembled complex. However both compounds were active against the cells lacking mitochondrial genome suggesting that the subunit a is not involved in the binding of the inhibitors. Considering the effective concentration (EC50) of these compounds and the concentration used for in vitro assays to exert the phenotype, these drugs get concentrated in the mitochondria or more cellular targets are involved in their cytotoxic mode of action.

Permanent Link: http://hdl.handle.net/11104/0282934