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Nephrotoxicity is one common side effect of the first line anti-leishmanial treatment, liposomal amphotericin B. Amphotericin B targets ergosterol, so one approach to reducing dose and side effects could be improving the access of the drug to its target. While the surface exposure of ergosterol in Leishmania is unknown, sterols in mammalian cells can be sheltered from sterol-binding agents by membrane components, including sphingolipids. Here, we tested the ability of the Leishmania major sphingolipids inositol phosphorylceramide (IPC), and ceramide to shelter ergosterol by preventing binding and cytotoxicity of the sterol-binding toxins streptolysin O and perfringolysin O using flow cytometry. In contrast to mammalian systems, Leishmania sphingolipids did not preclude toxin binding to sterols in the membrane. However, IPC interfered with cytotoxicity. Ceramide reduced perfringolysin O, but not streptolysin O, cytotoxicity in cells. Ceramide sensing was controlled by the toxin L3 loop. Ceramide was sufficient to protect L. major promastigotes from amphotericin B. These findings suggest that L. major offers a genetically tractable model organism for understanding toxin-membrane interactions. Furthermore, our findings suggest targeting ceramide may enhance the efficacy of ergosterol-targeting anti-leishmanial drugs.

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