Sitamaquine-resistance in Leishmania donovani affects drug accumulation and lipid metabolism

• Published in: Biomedicine & pharmacotherapy Vol. 68; no. 7; pp. 893 - 897
• Main Authors: Imbert, L, Cojean, S, Libong, D, Chaminade, P, Loiseau, P.M
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2014
• Subjects: Aminoquinolines - pharmacology; Antileishmanial drug; Antiprotozoal Agents - pharmacology; Biological Transport - physiology; Cell Membrane - metabolism; Cell Membrane - physiology; Choline Kinase - metabolism; Cytosol - metabolism; Cytosol - physiology; Drug Resistance - physiology; Drug resistance mechanisms; Ergosterol - metabolism; Internal Medicine; Leishmania donovani - drug effects; Leishmania donovani - metabolism; Leishmania donovani - physiology; Lipid Metabolism - physiology; Medical Education; Phosphatidylethanolamine N-Methyltransferase - metabolism; Phospholipids - metabolism; Sitamaquine; Antileishmanial drug; Drug resistance mechanisms; Sitamaquine
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2014.08.009

Abstract This study focuses on the mechanism of sitamaquine-resistance in Leishmania donovani . Sitamaquine accumulated 10 and 1.4 fold more in cytosol than in membranes of wild-type (WT) and of sitamaquine-resistant (Sita-R160) L. donovani promastigotes, respectively. The sitamaquine accumulation was a concentration-dependent process in WT whereas a saturation occurred in Sita-R160 suggesting a reduced uptake or an increase of the sitamaquine efflux. Membrane negative phospholipids being the main target for sitamaquine uptake, a lipidomic analysis showed that sitamaquine-resistance did not rely on a decrease of membrane negative phospholipid rate in Sita-R160, discarding the hypothesis of reduced uptake. However, sterol and phospholipid metabolisms were strongly affected in Sita-R160 suggesting that sitamaquine-resistance could be related to an alteration of phosphatidylethanolamine-N-methyl-transferase and choline kinase activities and to a decrease in cholesterol uptake and of ergosterol biosynthesis. Preliminary data of proteomics analysis exhibited different protein profiles between WT and Sita-160R remaining to be characterized.