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Hypericin, a natural compound fromHypericum perforatum (St. John's wort), has been identified as a specific inhibitor ofLeishmania donovani spermidine synthase (LdSS) using integrated computational and biochemical approaches. Hypericin showedin vitro inhibition of recombinant LdSS enzyme activity. Thein vivo estimation of spermidine levels inLeishmania promastigotes after hypericin treatment showed significant decreases in the spermidine pools of the parasites, indicating target specificity of the inhibitor molecule. The inhibitor, hypericin, showed significant antileishmanial activity, and the mode of death showed necrosis-like features. Further, decreased trypanothione levels and increased glutathione levels with elevated reactive oxygen species (ROS) levels were observed after hypericin treatment. Supplementation with trypanothione in the medium with hypericin treatment restoredin vivo trypanothione levels and ROS levels but could not prevent necrosis-like death of the parasites. However, supplementation with spermidine in the medium with hypericin treatment restoredin vivo spermidine levels and parasite death was prevented to a large extent. The data overall suggest that the parasite death due to spermidine starvation as a result of LdSS inhibition is not related to elevated levels of reactive oxygen species. This suggests the involvement of spermidine in processes other than redox metabolism inLeishmania parasites. Moreover, the work provides a novel scaffold, i.e., hypericin, as a potent antileishmanial molecule.

antimicrobial agents and chemotherapy

Probing the Molecular Mechanism of Hypericin-Induced Parasite Death Provides Insight into the Role of Spermidine beyond Redox Metabolism in Leishmania donovani