In Vitro Antiparasitic Activities of Monovalent Ionophore Compounds for Human and Canine Leishmaniases

SIMPLE SUMMARY: The leishmaniases are vector-borne, neglected diseases caused by parasites of the genus Leishmania, widely diffused around the globe. Clinical manifestations range from localized cutaneous and mucocutaneous lesions to the visceral form, with potentially fatal outcomes. Associated with malnutrition, a weak immune system, and no access to health-care facilities, these conditions affect the poorest populations worldwide. In addition, dogs develop a multisystemic and fatal disease, and act as the main parasite reservoir for some Leishmania species. Currently, human, and canine leishmaniases share the same treatment, which includes very few, difficult to administer, expensive, and toxic drugs. Moreover, drug resistance is increasingly spreading, and there is no human vaccine. Therefore, improved and safer treatments are a high priority. Here, monovalent ionophores (salinomycin, monensin, and nigericin) were repurposed in vitro for their leishmanicidal abilities against both insect-stage parasites (promastigotes) and intracellular forms (amastigotes) within human and primary canine macrophages. These compounds showed similar antiparasitic effects against distinct Leishmania spp. promastigotes. Interestingly, a differential and host-specific anti-amastigote efficacy was observed, being these compounds more active against human- than canine-infected macrophages. Altogether, these data indicate a potential application of ionophores against Leishmania infections and challenge the concept that the same compounds may be equally effective against both human and canine leishmaniases. ABSTRACT: The leishmaniases are vector-borne parasitic diseases affecting humans and animals, with high mortality rates in endemic countries. Infected dogs represent the main reservoir of infection. Disease control is mainly based on chemotherapy, which, at present, shows serious drawbacks both in humans and dogs. Therefore, the discovery or repurposing of new treatments is mandatory. Here, three monovalent ionophores (salinomycin, monensin, nigericin) were tested against promastigotes of Leishmania (L.) infantum, Leishmania tropica, and Leishmania braziliensis, and against amastigotes of L. infantum within human and, for the first time, canine macrophages. All three drugs were leishmanicidal against all Leishmania spp. promastigotes with IC(50) values between 7.98 and 0.23 µM. Monensin and nigericin showed IC(50) values < 1 µM, whereas salinomycin was the least active compound (IC(50) > 4 µM). Notably, the ionophores killed L. infantum amastigotes within human THP-1 cells with IC(50) values ranging from 1.67 to 1.93 µM, but they only reduced by 27–37% the parasite burden in L. infantum-infected canine macrophages, showing a host-specific efficacy. Moreover, a selective higher toxicity against canine macrophages was observed. Overall, repurposed ionophores have the potential to be further investigated as anti-Leishmania agents, but different drug options may be required to tackle human or canine leishmaniases.