Study of the effects of ubiquinone biosynthesis inhibition on the intraerythrocytic stages of Plasmodium falciparum

Abstract

Resistances to the different etiological treatments used for malaria have already arisen and so it is necessary to find new compounds and effective pharmaceutical combinations totreat this disease. One of the most recently discovered antimalarials is atovaquone (ATO), an effective competitive inhibitor with ubiquinol or reduced coenzyme Q (UQH2) for its binding in the mitochondrial bc1 complex. However, ATO needs to be combined with other compounds to achieve a clinical cure. Therefore, it is rational to think that the inhibition of ubiquinone (UQ) biosynthesis could be an interesting pharmacological target by itself and / or could significantly increase the ATO effectiveness. This project aims to evaluate if UQ is essential in the parasite by generation of knockout mutants and to look for inhibitors of the prenylquinone biosynthesis based on genomic deletion and the use of analogs of the isoprenic and aromatic substrates of the enzyme 4-hydroxybenzoate polyprenyltransferase (UbiA) involved in the UQ biosynthesis. Once effective inhibitors have been found, their cytotoxic effects will be studied in Vero cells (African Green Monkey Renal Cell Epithelial Cell) and Plasmodium in isolation or in combination with ATO. We attach promising preliminary results to this project. We believe that this project will help to better understand bioenergetic aspects of the parasite and could contribute to the development of new antimalarial drugs or pharmacological combinations to treat malaria and / or other diseases caused by ATO-sensitive pathogens. (AU)