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Alkyl galactofuranosides strongly interact with Leishmania donovani membrane and provide anti-leishmanial activity.
Auteur(s) : Suleman, Muhammad Gangneux, Jean-Pierre Legentil, Laurent Belaz, Sorya Cabezas, Yari Manuel, Christelle Dureau, Rémy Sergent, Odile
Auteurs secondaires : Institut de recherche, santé, environnement et travail [Rennes] (Irset) ; Université d'Angers (UA) - Université des Antilles et de la Guyane (UAG) - Université de Rennes 1 (UR1) - École des Hautes Études en Santé Publique [EHESP] (EHESP) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) Institut des Sciences Chimiques de Rennes (ISCR) ; Université de Rennes 1 (UR1) - Ecole Nationale Supérieure de Chimie de Rennes - Institut National des Sciences Appliquées (INSA) - Centre National de la Recherche Scientifique (CNRS) Service de Parasitologie-Mycologie [Rennes] ; Université de Rennes 1 (UR1) - Hôpital Pontchaillou - CHU Pontchaillou [Rennes] Biotechnologie et Gestion des Agents Pathogènes en agriculture (BioGAP) ; Institut Charles Viollette (ICV) - EA 7394 (ICV) ; Université de Lille, Sciences et Technologies - Université de Lille, Droit et Santé - Université d'Artois (UA) - Université du Littoral Côte d'Opale (ULCO) - Institut Supérieur d'Agriculture - Institut National de la Recherche Agronomique (INRA) - Université de Lille, Sciences et Technologies - Université de Lille, Droit et Santé - Université d'Artois (UA) - Université du Littoral Côte d'Opale (ULCO) - Institut Supérieur d'Agriculture - Institut National de la Recherche Agronomique (INRA) - Institut Supérieur d'Agriculture de Lille (Groupe ISA)

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
: We investigated the in vitro effects of four alkyl-galactofuranoside derivatives, i.e. octyl-β-D-galactofuranoside (1), 6-amino-β-D-galactofuranoside (2), 6-N-acetamido-β-D-galactofuranoside (3), and 6-azido-β-D-galactofuranoside (4) on Leishmania donovani. Their mechanism of action was explored using electron paramagnetic resonance spectroscopy (EPR) and nuclear magnetic resonance (NMR), and ultrastructural alterations by transmission electron microscopy (TEM). Compound 1 showed the most promising effects by inhibiting promastigote growth at IC50 8.96 ± 2.5 μM. All compounds exhibit low toxicity towards human macrophages. Compound 1 had a higher selectivity index than the comparative molecule used, i.e. miltefosine (159.7 versus 37.9, respectively). EPR showed that compound 1 significantly reduced membrane fluidity, compared to control promastigotes and to compound 3. The furanose ring was shown to support this effect since the isomer galactopyranose had no effect on parasite membrane fluidity or growth. NMR showed a direct interaction of all compounds (1>2>3>4) with the promastigote membrane, as well as with octyl-galactopyranose and octanol, providing evidence that the n-octyl chain was primarily involved in the anchoring with the parasite membrane, followed by the putative crucial role of furanose ring in the anti-leishmanial activity. A morphologic analysis of compound 1-treated promastigotes by TEM revealed profound alterations on parasite membrane and organelles, but not with compound 3. Quantification of annexinV binding by flow cytometry confirmed that compound 1 induced apoptosis in >90% promastigotes. The effect of compound 1 was also assessed on intra-macrophagic amastigotes, and showed a reduction in amastigote growth associated with an increase of ROS production, thus validating its promising effect.
ISSN: 0066-4804

hal-00941772
https://hal.archives-ouvertes.fr/hal-00941772
PUBMED : 24468785
DOI : 10.1128/AAC.01350-13

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