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

Le résumé fourni par la source

Chagas disease is an endemic American parasitosis, caused byTrypanosoma 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 againstT. bruceiandLeishmaniaspp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug onT. cruziand other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation ofT. cruziepimastigotes 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 inPhytomonas jma 066andLeishmania mexicanaproliferation but not inCrithidia 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 silicostudies 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 inT. cruziand suggest IVM as a good candidate for drug repurposing in the Chagas disease context.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.