RESUMEN
Neglected 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 from Streptomyces, 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 against Trypanosoma brucei and Leishmania donovani, but much less so against Trypanosoma evansi. Using fluorescence microscopy, we observed a rapid loss of the mitochondrial membrane potential in T. brucei bloodstream forms upon venturicidin A treatment. Additionally, we report the loss of mitochondrial DNA in approximately 40%-50% of the treated parasites. We conclude that venturicidin A targets the ATP synthase of T. brucei, and we suggest that this macrolide could be a candidate for anti-trypanosomatid drug repurposing, drug combinations, or medicinal chemistry programs.
Asunto(s)
ADN de Cinetoplasto , Macrólidos , Potencial de la Membrana Mitocondrial , Trypanosoma brucei brucei , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma brucei brucei/genética , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Macrólidos/farmacología , ADN de Cinetoplasto/genética , ADN de Cinetoplasto/efectos de los fármacos , Tripanocidas/farmacología , Leishmania donovani/efectos de los fármacos , Leishmania donovani/genética , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/efectos de los fármacosRESUMEN
Fusarium graminearum, which causes Fusarium head blight (FHB) in cereals, is one of the most devastating fungal diseases by causing great yield losses and mycotoxin contamination. A major bioactive ingredient, venturicidin A (VentA), was isolated from Streptomyces pratensis S10 mycelial extract with an activity-guided approach. No report is available on antifungal activity of VentA against F. graminearum and effects on deoxynivalenol (DON) biosynthesis. Here, VentA showed a high antagonistic activity toward F. graminearum with an EC50 value of 3.69 µg/mL. As observed by scanning electron microscopy, after exposure to VentA, F. graminearum conidia and mycelia appeared abnormal. Different dyes staining revealed that VentA increased cell membrane permeability. In growth chamber and field trials, VentA effectively reduced disease severity of FHB. Moreover, VentA inhibited DON biosynthesis by reducing pyruvic acid, acetyl-CoA production, and accumulation of reactive oxygen species (ROS) and then inhibiting trichothecene (TRI) genes expression and toxisome formation. These results suggest that VentA is a potential fungicide for controlling FHB.