Revisiting the mode of action of the antimalarial proguanil using the yeast model

Pierre Mounkoro (1) , Thomas Michel (1) , Brigitte Meunier (1, 2)

1 I2BC - Institut de Biologie Intégrative de la Cellule
2 CNRS - Centre National de la Recherche Scientifique

Proguanil in combination with its synergistic partner atovaquone has been used for malaria treatment and prophylaxis for decades. However its mode of action is not fully understood. Here we used yeast to investigate its activity. Proguanil inhibits yeast growth, causes cell death and acts in synergy with atovaquone. It was previously proposed that the drug would target the system that maintains the mitochondrial membrane potential when the respiratory chain is inhibited. However our data did not seem to validate that hypothesis. We proposed that proguanil would not have a specific target but accumulate in the mitochondrial to concentrations that impair multiple mitochondrial functions leading to cell death. Selection and study of proguanil resistant mutants pointed towards an unexpected resistance mechanism: the decrease of CoQ level, which possibly alters the mitochondrial membrane properties and lowers proguanil intramitochondrial level.

Mots clés: antimalarial drug; mitochondrial function; drug mode of action; drug resistance; yeast model

Domaines: Sciences du Vivant [q-bio]; Biochimie, Biologie Moléculaire

Pierre Mounkoro, Thomas Michel, Brigitte Meunier. Revisiting the mode of action of the antimalarial proguanil using the yeast model. Biochemical and Biophysical Research Communications, 2021, 534, pp.94-98. ⟨10.1016/j.bbrc.2020.12.004⟩. ⟨hal-03054347⟩