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Theses

Développement d’outils chimiométriques pour l’étude des traitements antileishmaniens

Abstract : Leishmaniasis is a more and more spreading disease, and resistance of parasites toward antileishmanial drugs is a concern for public safety organizations troughout the world. Miltefosine is the only oral drug, and its mechanism of action implies membrane lipids, and phospholipids, of parasite cells.In order to assess this mechanism of action, and resistance mechanisms developed, a lipidomic study of Leishmania donovani strains (treated, resistant, treated-resistant) was performed in the present work. A Normal-Phase High-Performance Liquid Chromatography (NP-HPLC) was coupled to an ElectroSpray Ionisation Mass Spectrometer (ESI-MS) to analyze phospholipids, and data were computed using an Orthogonal Signal Correction-Partial Least Squares-Discriminant Analysis (OSC-PLS-DA). Molecular species responsible for the differenciation of strains were then structuraly identified using tandem mass spectrometry. Hypotheses on metabolic pathways implied were then proposed.The study was then extended to a broader range of lipids, also analyzed through NP-HPLC-MS. A comparison of Atmospheric Pressure Ion sources (ESI, Atmospheric Pressure Chemical Ionization and Atmospheric Pressure PhotoIonization) was thus necessary in order to select the most suitable source. A lipidomic study was then performed to assess mechanisms of action and mechanisms of resistance concerning miltefosine and Amphotericin B.
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Laurent Imbert. Développement d’outils chimiométriques pour l’étude des traitements antileishmaniens. Autre. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA112010⟩. ⟨tel-00685887⟩

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