Broadening the spectrum of ivermectin: its effect on Trypanosoma cruzi and related trypanosomatids

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dc.citation.titleFrontiers in Cellular and Infection Microbiology
dc.citation.volume1-10
dc.citation.volume12
dc.creatorFraccaroli, Laura
dc.creatorRuiz, María Daniela
dc.creatorPerdomo, Virginia Gabriela
dc.creatorClausi, Agustina Nicole
dc.creatorBalcazar, Darío Emmanuel
dc.creatorLarocca, Luciana
dc.creatorCarrillo, Carolina
dc.date.accessioned2024-04-29T13:42:37Z
dc.date.available2024-04-29T13:42:37Z
dc.date.issued2022-07-28
dc.description.abstractChagas disease is an endemic American parasitosis, caused by Trypanosoma cruzi. The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects. Thus, there is a need to develop new trypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drug with low human and veterinary toxicity with effects against T. brucei and Leishmania spp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug on T. cruzi and other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation of T. cruzi epimastigotes as well as the amastigotes and trypomastigotes survival. The Selectivity Index for the amastigote stage with respect to Vero cells was 12. The IVM effect was also observed in Phytomonas jma 066 and Leishmania mexicana proliferation but not in Crithidia fasciculata. On the epimastigote stage, the IVM effect was trypanostatic at 50 μM but trypanocidal at 100 μM. The assays of the drug combinations of IVM with BNZ or NFX showed mainly additive effects among combinations. In silico studies showed that classical structures belonging to glutamate-gated Cl channels, the most common IVM target, are absent in kinetoplastids. However, we found in the studied trypanosomatid genomes one copy for putative IMPα and IMPβ, potential targets for IVM. The putative IMPα genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMPβ binding sequence. These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.
dc.description.filFil: Fraccaroli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Ciencia y Tecnología César Milstein (ICT). Laboratorio de Biología Molecular y Bioquímica; Argentina.
dc.description.filFil: Ruiz, María Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Ciencia y Tecnología César Milstein (ICT). Laboratorio de Biología Molecular y Bioquímica; Argentina.
dc.description.filFil: Clausi, Agustina Nicole. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Ciencia y Tecnología César Milstein (ICT). Laboratorio de Biología Molecular y Bioquímica; Argentina.
dc.description.filFil: Larocca, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Ciencia y Tecnología César Milstein (ICT). Laboratorio de Biología Molecular y Bioquímica; Argentina.
dc.description.filFil: Carrillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Ciencia y Tecnología César Milstein (ICT). Laboratorio de Biología Molecular y Bioquímica; Argentina.
dc.description.filFil: Perdomo, Virginia Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Parasitología; Argentina.
dc.description.filFil: Balcazar, Darío Emmanuel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Parasitología; Argentina.
dc.description.sponsorshipInstituto de Ciencia y Tecnología César Milstein (ICT)
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
dc.description.sponsorshipThe National Agency of Scientific and Technological Promotion: PICT 2015-0962, PICT 2018-1124
dc.identifier.issn2235-2988
dc.identifier.urihttps://hdl.handle.net/2133/26964
dc.language.isoen
dc.publisherFrontiers Media
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fcimb.2022.885268/full
dc.relation.publisherversionhttps://doi.org/10.3389/fcimb.2022.885268
dc.rightsopenAccess
dc.rights.holderFraccaroli, Laura
dc.rights.holderRuiz, María Daniela
dc.rights.holderPerdomo, Virginia Gabriela
dc.rights.holderClausi, Agustina Nicole
dc.rights.holderBalcazar, Darío Emmanuel
dc.rights.holderLarocca, Luciana
dc.rights.holderCarrillo, Carolina
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectChagas disease
dc.subjectIvermectin
dc.subjectDrug repurposing
dc.subjectTrypanocidal drug
dc.subjectDrug combination
dc.subjectTrypanosoma cruzi
dc.titleBroadening the spectrum of ivermectin: its effect on Trypanosoma cruzi and related trypanosomatids
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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