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

Objectives The present study was designed to elucidate the mechanism of tafenoquine uptake in Leishmania and its sterol dependence. Methods Because tafenoquine is a fluorescent compound, spectrofluorimetric analysis allowed us to monitor its uptake by Leishmania promastigotes and intracellular amast...

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Published in:Journal of antimicrobial chemotherapy 2011-11, Vol.66 (11), p.2562-2565
Main Authors: Manzano, José Ignacio, Carvalho, Luis, García-Hernández, Raquel, Poveda, José Antonio, Ferragut, José Antonio, Castanys, Santiago, Gamarro, Francisco
Format: Article
Language:English
Subjects:
Aminoquinolines - metabolism
Aminoquinolines - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiprotozoal Agents - metabolism
Antiprotozoal Agents - pharmacology
beta-Cyclodextrins - pharmacology
Biological and medical sciences
Biological Transport
Cell Membrane - metabolism
Cholesterol Oxidase - metabolism
Diffusion
Hydrogen-Ion Concentration
Leishmania
Leishmania major - drug effects
Leishmania major - growth & development
Leishmania major - metabolism
Medical sciences
Pharmacology
Pharmacology. Drug treatments
Prescription drugs
Protozoa
Sterols
Sterols - metabolism
Temperature
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Summary:Objectives The present study was designed to elucidate the mechanism of tafenoquine uptake in Leishmania and its sterol dependence. Methods 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. Results 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. Conclusions 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.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dkr345