Repurposing strategy of atorvastatin against Trypanosoma cruzi: in vitro monotherapy and combined therapy with benznidazole exhibits synergistic trypanocidal activity [PublishAheadOfPrint]

Statins are inhibitors of cholesterol synthesis but other biological properties, like antimicrobial effects, have been assigned leading to the designation of their pleiotropic aspect. Our goal was investigate the activity and selectivity of atorvastatin (AVA) against T. cruzi using in vitro models aiming more effective and safer therapeutic options through drug repurposing proposals under monotherapy and in combination with benznidazole (BZ). Phenotypic screening used different strains (Tulahuen (DTU VI) and Y (DTU II)) and forms (intracellular forms, bloodstream and tissue-derived trypomastigotes) of the parasite. While assaying Tulahuen strain, AVA is more active against intracellular amastigotes (SI=3). Also, against another parasite DTU (Y strain), this statin was more active (2.1-fold) and selective (2.4-fold) against bloodstream trypomastigotes (SI=51) than upon the intracellular forms (SI=20). The cytomorphological approach using phalloidin–TRITC permitted to verify that AVA did not induced cell density reduction and CC maintained their typical cytoarchitecture. Combinatory approaches using fixed-ratio methods showed that AVA and BZ gave synergistic interactions against both trypomastigotes and intracellular forms (mean FICIs = 0.46 ± 0.12 and 0.48 ± 0.03 respectively). In this sense, the repurposing strategy of AVA, especially in combination with BZ leading to a synergic effect, encourages future studies in order to identify novel therapeutic protocols for Chagas disease treatment.

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