Repurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity

dc.creatorLima, C. F. Araujo
dc.creatorPeres, R. B.
dc.creatorSilva, P. B.
dc.creatorBatista, M. M.
dc.creatorAiub, C. A. F.
dc.creatorFelzenszwalb, I.
dc.creatorSoeiro, Maria Nazaré C.
dc.date2019-01-24T15:53:41Z
dc.date2019-01-24T15:53:41Z
dc.date2018
dc.date.accessioned2023-09-26T20:22:30Z
dc.date.available2023-09-26T20:22:30Z
dc.identifierLIMA, C. F. Araujo; et al. Repurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity. Antimicrobial Agents and Chemotherapy, v.62, n.9, e00979-18, Sept. 2018.
dc.identifier0066-4804
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/31302
dc.identifier10.1128/AAC.00979-18
dc.identifier1098-6596
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8855462
dc.descriptionStatins are inhibitors of cholesterol synthesis, but other biological properties, such as antimicrobial effects, have also been assigned to them, leading to their designation as pleiotropic agents. Our goal was to investigate the activity and selectivity of atorvastatin (AVA) against Trypanosoma cruzi by using in vitro models, aiming for more effective and safer therapeutic options through drug repurposing proposals for monotherapy and therapy in combination with benznidazole (BZ). Phenotypic screening was performed with different strains (Tulahuen [discrete typing unit {DTU} VI] and Y [DTU II]) and forms (intracellular forms, bloodstream trypomastigotes, and tissue-derived trypomastigotes) of the parasite. On assay of the Tulahuen strain, AVA was more active against intracellular amastigotes (selectivity index [SI] = 3). Also, against a parasite of another DTU (Y strain), this statin was more active (2.1-fold) and selective (2.4-fold) against bloodstream trypomastigotes (SI = 51) than against the intracellular forms (SI = 20). A cytomorphological approach using phalloidin-rhodamine permitted us to verify that AVA did not induced cell density reduction and that cardiac cells (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 sums of fractional inhibitory concentration indexes [∑FICIs] of 0.46 ± 0.12 and 0.48 ± 0.03, respectively). Thus, the repurposing strategy for AVA, especially in combination with BZ, which leads to a synergistic effect, is encouraging for future studies to identify novel therapeutic protocols for Chagas disease treatment.
dc.formatapplication/pdf
dc.languageeng
dc.publisherAmerican Society for Microbiology
dc.rightsopen access
dc.subjectTripanocida
dc.subjectDoença de Chagas
dc.subjectQuimioterapia experimental
dc.subjectSeletividade
dc.subjectEstatina
dc.subjectAtorvastatina
dc.subjectCombined therapy
dc.subjectTrypanocidal
dc.subjectChagas Disease
dc.subjectExperimental chemotherapy
dc.subjectSselectivity
dc.subjectStatin
dc.subjectAtorvastatin
dc.subjectHMGCR inhibitor
dc.subjectCombined therapy
dc.titleRepurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity
dc.typeArticle


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