SQ109 inhibits proliferation of Leishmania donovani by disruption of intracellular Ca 2+ homeostasis, collapsing the mitochondrial electrochemical potential (ΔΨ m) and affecting acidocalcisomes

Parasitol Res. 2020 Feb;119(2):649-657. doi: 10.1007/s00436-019-06560-y. Epub 2020 Jan 2.

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 (ΔΨm). 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 ΔΨm 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.

Keywords: Acidocalcisomes; Anti-tuberculosis drugs; Calcium; Leishmania donovani; Mitochondria; SQ109; Visceral leishmaniasis.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Animals
  • Cell Proliferation
  • Chagas Disease / drug therapy
  • Cytoplasm
  • Ethylenediamines / pharmacology*
  • Humans
  • Leishmania donovani / drug effects*
  • Leishmania mexicana / drug effects
  • Leishmaniasis, Cutaneous / drug therapy*
  • Leishmaniasis, Cutaneous / parasitology
  • Leishmaniasis, Visceral / drug therapy*
  • Leishmaniasis, Visceral / parasitology
  • Macrophages / parasitology
  • Membrane Potential, Mitochondrial / drug effects*
  • Mitochondria
  • Trypanosoma cruzi / drug effects

Substances

  • Ethylenediamines
  • N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine
  • Adamantane