Tuberculosis drug candidate attacks parasites three ways

Parasitic infections such as leishmaniasis remain a major global health problem, especially when parasites live inside human cells where many drugs struggle to reach them. To search for new options, Akanksha M. Pandey and colleagues tested a tuberculosis drug candidate, SQ109 ( 8a ), and a closely related analog, MeSQ109 ( 8b ), against the parasite Leishmania mexicana. The team looked at both free-living promastigote forms and the disease-causing amastigote forms that live inside host macrophages. They also measured how toxic the compounds were to the host cells themselves. The study set out to identify not only whether these molecules could kill parasites but also how they worked inside the parasite and whether they changed how host immune cells behaved. By testing the drugs against parasites grown in culture and inside macrophages, the researchers could compare direct anti-parasitic effects with any contributions from host cells. The work aimed to determine whether SQ109 and MeSQ109 could be repurposed from tuberculosis research into new anti-parasitic therapies and to map their mechanisms of action.

The experiments showed striking results for MeSQ109 ( 8b ). Against intracellular forms of Leishmania mexicana the compound had potent activity (1.7 nM) and relatively low toxicity to host macrophages (∼61 µM), giving a selectivity index of ∼36,000. Mechanistic studies revealed that MeSQ109 targeted parasite mitochondria and collapsed the proton motive force, and it also targeted acidocalcisomes, rapidly increasing the intracellular Ca 2+ concentration. To probe the ability of SQ109 ( 8a ) and related molecules to disrupt proton gradients, the team used an E. coli inverted membrane vesicle assay to measure pH gradient collapse for SQ109 and 17 analogs. They found a significant correlation, on average R=0.67, p∼0.008, between pH gradient collapse and cell growth inhibition in Trypanosoma brucei, T. cruzi, L. donovani and Plasmodium falciparum. The study also examined pH gradient collapse with other anti-leishmanial agents including azoles, antimonials, benzofurans, amphotericin B and miltefosine. Notably, the enhanced activity against intracellular trypanosomatids was seen with Leishmania spp. grown in macrophages but not with Trypanosoma cruzi in epithelial cells, a difference the authors propose is partly due to host-based killing. This idea is supported by recent observations that SQ109 is known to convert macrophages to a pro-inflammatory (M1) phenotype.

Taken together, the findings suggest these anti-parasitic effects come from a combination of direct parasite targeting and host-cell mediated killing. By collapsing the proton motive force and disrupting acidocalcisome function to raise intracellular Ca 2+, MeSQ109 ( 8b ) appears to undercut essential parasite bioenergetics and ion homeostasis. At the same time, converting macrophages toward a pro-inflammatory (M1) phenotype could boost the host’s ability to clear intracellular parasites, explaining why activity was stronger in macrophage-grown Leishmania. The correlation between pH gradient collapse in the E. coli inverted membrane vesicle assay and growth inhibition across several parasites points to the proton motive force as a shared vulnerability among diverse protozoa. Because SQ109 ( 8a ) began as a tuberculosis drug candidate, these results raise the possibility of repurposing or modifying such molecules for diseases like leishmaniasis, trypanosomiasis and malaria. Further work will be needed to confirm safety and efficacy in whole-animal models and to define how best to combine direct anti-parasitic actions with host-directed immune responses.