title: Sitamaquine-resistance in Leishmania donovani affects drug accumulation and lipid metabolism.
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.
authors.affiliation: Université Paris-Sud, UMR 8076, Chimiothérapie Antiparasitaire, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France; Université Paris-Sud, Groupe Chimie Analytique Paris-Sud, EA 4041, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France.
authors.forename: L
authors.initials: L
authors.lastname: Imbert
authors.affiliation: Université Paris-Sud, UMR 8076, Chimiothérapie Antiparasitaire, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France.
authors.forename: S
authors.initials: S
authors.lastname: Cojean
authors.affiliation: Université Paris-Sud, Groupe Chimie Analytique Paris-Sud, EA 4041, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France.
authors.forename: D
authors.initials: D
authors.lastname: Libong
authors.affiliation: Université Paris-Sud, Groupe Chimie Analytique Paris-Sud, EA 4041, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France.
authors.forename: P
authors.initials: P
authors.lastname: Chaminade
authors.affiliation: Université Paris-Sud, UMR 8076, Chimiothérapie Antiparasitaire, Faculté de Pharmacie, 5, rue Jean-Baptiste-Clément, 92296 Châtenay-Malabry, France. Electronic address: philippe.loiseau@u-psud.fr.
authors.forename: P M
authors.initials: PM
authors.lastname: Loiseau
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D002797:Choline Kinase / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000502:physiology; D004351:Drug Resistance / Q000502:physiology*; D004875:Ergosterol / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D000981:Antiprotozoal Agents; D010743:Phospholipids; D050918:Phosphatidylethanolamine N-Methyltransferase; D002797:Choline Kinase; C080436:8-aminoquinoline; D004875:Ergosterol
keywords: Antileishmanial drug; Drug resistance mechanisms; Sitamaquine