SQ109 inhibits proliferation of Leishmania donovani by disruption of intracellular Ca²⁺ homeostasis, collapsing the mitochondrial electrochemical potential (ΔΨ_m) and affecting acidocalcisomes

Abstract

Leishmania donovani is the causative agent of visceral leishmaniasis. Annually, 500 million new cases of infection are reported mainly in poor communities, decreasing the interest of the pharmaceutical industries. Therefore, the repositioning of new drugs is an ideal strategy to fight against these parasites. SQ109, a compound in phase IIb/III of clinical trials to treat resistant Mycobacterium tuberculosis, has a potent effect against Trypanosoma cruzi, responsible for Chagas’ disease, and on Leishmania mexicana, the causative agent of cutaneous and muco-cutaneous leishmaniasis. In the latter, the toxic dose against intramacrophagic amastigotes is very low (IC₅₀ ~ 11 nM). The proposed mechanism of action on L. mexicana involves the disruption of the parasite intracellular Ca²⁺ homeostasis through the collapse of the mitochondrial electrochemical potential (ΔΨ_m). In the present work, we show a potent effect of SQ109 on L. donovani, the parasite responsible for visceral leishmaniasis, the more severe and uniquely lethal form of these infections, obtaining a toxic effect on amastigotes inside macrophages even lower to that obtained in L. mexicana (IC₅₀ of 7.17 ± 0.09 nM) and with a selectivity index > 800, even higher than in L. mexicana. We also demonstrated for first time that SQ109, besides collapsing ΔΨ_m of the parasite, induced a very rapid damage to the parasite acidocalcisomes, essential organelles involved in the bioenergetics and many other important functions, including Ca²⁺ homeostasis. Both effects of the drug on these organelles generated a dramatic increase in the intracellular Ca²⁺ concentration, causing parasite death.