Potential efficacy of repurposed drugs for treating drug-resistant visceral leishmaniasis

Visceral leishmaniasis is a life-threatening parasitic disease that predominantly affects socioeconomically backward populations in the Indian subcontinent. Increasing rates of treatment relapse and reduced drug susceptibility among Leishmania donovani parasites have emerged as major challenges in endemic regions. In addition, immunosuppressive conditions further increase susceptibility to infection and complicate disease management. Current therapeutic options are limited by drug resistance, toxicity, high treatment costs, and the persistence of post-treatment complications. Drug repurposing offers a promising strategy by identifying new antileishmanial applications for existing drugs with established safety profiles. Therefore, this study evaluated the efficacy of Artemisinin, Chloroquine, Disulfiram, and Buparvaquone against clinical isolates of Leishmania donovani with reduced susceptibility to Miltefosine. The study is aimed at addressing the treatment failure and drug resistance among the Leishmania donovani clinical isolates. Due to the emergence of resistance among the clinical isolates, this study has focused on alternative medicines by considering drug repurposing. The in vitro efficacy of Artemisinin (ART), Chloroquine (CQ), Disulfiram (DIS), and Buparvaquone (BQ) was tested against both promastigote and amastigote stages of L. donovani CI (clinical isolates) that are less susceptible to Miltefosine and Amphotericin B, and their IC50 values were determined via MTT assays. The toxicity of the repurposed drugs was analyzed against PBMCs. All the repurposed drugs exhibited significant antileishmanial activity. Among these drugs, Buparvaquone was effective against the promastigote stage, with the lowest IC50 of 2.67 ± 0.15 nM, and against the amastigote stage, with an IC50 of 1.839 ± 0.228 nM. Compared to other drugs, Buparvaquone showed the highest efficacy against both the promastigote and amastigote stage of L. donovani Clinical isolate and all the repurposed drugs are cytotoxically safe. This study reports the potential efficacy of Artemisinin (ART), Chloroquine (CQ), Disulfiram (DIS), and Buparvaquone (BQ) for treating drug-resistant visceral leishmaniasis. Their in vitro efficacy and ability to modulate the immune response underscore their therapeutic promise. Further in vivo studies and clinical trials are recommended to confirm these findings and pave the way for new treatment formulations against susceptible strains of Leishmania donovani (Ld).