Journal of Antimicrobial Chemotherapy 2011-11-01

Uptake of the antileishmania drug tafenoquine follows a sterol-dependent diffusion process in Leishmania.

José Ignacio Manzano, Luis Carvalho, Raquel García-Hernández, José Antonio Poveda, José Antonio Ferragut, Santiago Castanys, Francisco Gamarro

Index: J. Antimicrob. Chemother. 66(11) , 2562-5, (2011)

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Abstract

The present study was designed to elucidate the mechanism of tafenoquine uptake in Leishmania and its sterol dependence.Because tafenoquine is a fluorescent compound, spectrofluorimetric analysis allowed us to monitor its uptake by Leishmania promastigotes and intracellular amastigotes, and to evaluate the effect of temperature, energy and H+ gradient on drug entry. The influence of sterols on tafenoquine uptake in Leishmania parasites was determined in experiments using sterol-depleting agents such as methyl-β-cyclodextrin or cholesterol oxidase.Tafenoquine exhibited fast entry kinetics into Leishmania in an energy-independent, but pH- and temperature-dependent, non-saturable process. Furthermore, sterol depletion decreased tafenoquine uptake.These findings suggest that Leishmania takes up tafenoquine by a diffusion process and that decreases in membrane sterol content may induce a decrease in drug uptake.