Retinoic acid shows direct parasiticidal activity by targeting ergosterol pathway in Leishmania donovani: a potential therapeutic advancement

Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania donovani parasite in Indian subcontinent and is life-threatening. It primarily inflicts the malnourished population. There is little therapeutic advancement in the last one decade or more, as the available drugs show adverse effects, complex long treatment, high cost and drug resistance. Here, in a concerted approach, we intended to address the malnutrition as well as the parasite load with a single modality. Our earlier findings show the protective effects of retinoic acid (RA) in controlling the parasite load in infected macrophages (m phi) and restores their M1 phenotype. RA also restores the levels of cellular cholesterol in infected m phi. In this process, we observed loss of ergosterol in the parasite upon treatment with RA. Hence, we hypothesized that RA, besides boosting the parasiticidal mechanism in m phi, may also target the sterol pathway in the parasite by targeting sterol 24-C methyltransferase (SMT). SMT plays an essential role in the formation of ergosterol, required for growth and viability in Leishmania species. Therefore, we predicted as well as validated the 3D structure of SMT protein and performed the quality check. RA showed -9.9 free binding energy towards SMT which is higher than any of its derivatives. The molecular dynamics showed stable conjugate and the in vitro testing showed a reduction by similar to twofold in the parasite number upon RA treatment. Importantly, it showed a loss of ergosterol possibly due to the inhibition of SMT protein. Our finding showed direct parasiticidal function of RA which is of significance in terms of therapeutic advancement.Communicated by Ramaswamy H. Sarma

Automated summary

This study discovered the parasiticidal function of retinoic acid (RA) in infected macrophages and its ability to restore cellular cholesterol levels. It also found that RA can interfere with the growth and viability of the parasite by inhibiting sterol 24-C methyltransferase (SMT), leading to a loss of cellular ergosterol.