ubiquinone and azoxystrobin

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.

Topics: Antimalarials; Atovaquone; Drug Resistance, Fungal; Drug Synergism; Drug Therapy, Combination; Membrane Potential, Mitochondrial; Mutation; Oxygen; Proguanil; Pyrimidines; Strobilurins; Ubiquinone; Vitamin K 3; Yeasts

Topics: Acrylates; Adenosine Triphosphate; Binding Sites; Chlorella vulgaris; Coumarins; Dose-Response Relationship, Drug; Electron Transport Complex III; Fungicides, Industrial; Molecular Docking Simulation; Oxidation-Reduction; Pyrimidines; Strobilurins; Toxicity Tests, Acute; Ubiquinone; Water Pollutants, Chemical