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

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