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

FRACCAROLI LAURA; RUIZ DANIELA; PERDOMO VIRGINIA GABRIELA; CLAUSI AGUSTINA NICOLE; BALCAZAR DARIO; CARILLO CAROLINA

Frontiers in Cellular and Infection Microbiology

Frontiers Media S.A.

Lugar: Lausanne ; Año: 2022

Chagas disease is an endemic American parasitosis, caused by Trypanosomacruzi. The current therapies, benznidazole (BZN) and nifurtimox (NFX), showlimited efficacy and multiple side effects. Thus, there is a need to develop newtrypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drugwith low human and veterinary toxicity with effects against T. brucei andLeishmania spp. Considering this and its relatively low cost, we evaluate IVMas a potential repurposed trypanocidal drug on T. cruzi and othertrypanosomatids. We found that IVM affected, in a dose-dependent manner,the proliferation of T. cruzi epimastigotes as well as the amastigotes andtrypomastigotes survival. The Selectivity Index for the amastigote stage withrespect to Vero cells was 12. The IVM effect was also observed in Phytomonasjma 066 and Leishmania mexicana proliferation but not in Crithidia fasciculata.On the epimastigote stage, the IVM effect was trypanostatic at 50 mM buttrypanocidal at 100 mM. The assays of the drug combinations of IVM with BNZor NFX showed mainly additive effects among combinations. In silico studiesshowed that classical structures belonging to glutamate-gated Cl channels, themost common IVM target, are absent in kinetoplastids. However, we found inthe studied trypanosomatid genomes one copy for putative IMPa and IMPb,potential targets for IVM. The putative IMPa genes (with 76% similarity) showedconserved Armadillo domains but lacked the canonical IMPb binding sequence.These results allowed us to propose a novel molecular target in T. cruzi andsuggest IVM as a good candidate for drug repurposing in the Chagasdisease context.