Sitamaquine-resistance in Leishmania donovani affects drug accumulation and lipid metabolism.
Biomed Pharmacother
; 68(7): 893-7, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-25201056
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leishmania donovani
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Resistência a Medicamentos
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Metabolismo dos Lipídeos
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Aminoquinolinas
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article