Host cholesterol influences the activity of sterol biosynthesis inhibitors in Leishmania amazonensis

Abstract

A significant percentage of exogenous cholesterol was found in promastigotes and amastigotes of all studied species of Leishmania, suggesting a biological role for this molecule. Previous studies have shown that promastigotes of Leishmania uptake more low-density lipoprotein (LDL) particles under pharmacological pressure and are more susceptible to ergosterol inhibition in the absence of exogenous sources of cholesterol. This work shows that the host's LDL is available to intracellular amastigotes and that the absence of exogenous cholesterol enhances the potency of sterol biosynthesis inhibitors in infected macrophages. A complete understanding of cholesterol transport to the parasitophorous vacuole can guide the development of a new drug class to be used in combination with sterol biosynthesis inhibitors for the treatment of leishmaniases.

Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum

“…Of note, intracellular Leishmania can take up cholesterol from the host-cell membrane 22 or by direct fusion with endocytic vacuoles containing LDL particles. 40 Otherwise, cholesterol and sphingolipids are important regulators of lysosomal membrane trafficking and fusion. The SNARE complexes, which mediate membrane fusion, are largely associated with cholesterol-rich domains in membranes.…”