Venturicidin A affects the mitochondrial membrane potential and induces kDNA loss inTrypanosoma brucei

Abstract

AbstractNeglected tropical diseases caused by trypanosomatid parasites have devastating health and economic consequences, especially in tropical areas. New drugs or new combination therapies to fight these parasites are urgently needed. Venturicidin A, a macrolide extracted fromStreptomyces, inhibits the ATP synthase complex of fungi and bacteria. However, its effect on trypanosomatids is not fully understood. In this study, we tested venturicidin A on a panel of trypanosomatid parasites using Alamar Blue assays and found it to be highly active againstTrypanosoma bruceiandLeishmania donovani, but much less so againstTrypanosoma evansi. Using fluorescence microscopy we observed a rapid loss of the mitochondrial membrane potential inT. bruceibloodstream forms upon venturicidin A treatment. Additionally, we report the loss of the mitochondrial DNA in approximately 40 to 50% of the treated parasites. We conclude that venturicidin A targets the ATP synthase ofT. brucei, and we suggest that this macrolide could be a candidate for antitrypanosomatid drug repurposing, drug combinations, or medicinal chemistry programs.