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JAC Advance Access originally published online on September 12, 2009
Journal of Antimicrobial Chemotherapy 2009 64(5):993-1001; doi:10.1093/jac/dkp321
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Membrane sterol depletion impairs miltefosine action in wild-type and miltefosine-resistant Leishmania donovani promastigotes

M. Saint-Pierre-Chazalet1,2,3,4, M. Ben Brahim1,2, L. Le Moyec4,5, C. Bories1,2, M. Rakotomanga1,2 and P. M. Loiseau1,2,*

1 Université Paris-Sud, UMR 8076, Chimiothérapie Antiparasitaire, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, Chatenay-Malabry, F-92296, France 2 CNRS, Chatenay-Malabry, F-92296, France 3 UPMC Université Paris 06, BioMoCeTi, Genopole Campus 1, 5 rue Henri Desbruères, 91030 Evry cedex, France 4 CNRS UMR 7033, BioMoCeTi, Genopole Campus 1, 5 rue Henri Desbruères, 91030 Evry cedex, France 5 Université Paris 13, UFR SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France

Received 1 April 2009; returned 3 June 2009; revised 24 July 2009; accepted 3 August 2009

* Corresponding author. Université Paris-Sud, UMR 8076, Laboratoire de Chimie des Substances Naturelles et Chimiothérapie Antiparasitaire, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, Chatenay-Malabry, F-92296, France. Tel: +33-1-46-83-55-53; Fax: +33-1-46-83-55-57; E-mail: philippe.loiseau{at}u-psud.fr

Objectives: This study focuses on the importance of sterols in the action of miltefosine (hexadecylphosphocholine, HePC) against Leishmania donovani.

Methods: Plasma membranes of L. donovani promastigotes were depleted of sterol using methyl-β-cyclodextrin (MCD) and cholesterol oxidase (CH-OX). Sterols were quantified and HePC susceptibility was assessed using the MTT test. A biomimetic model of the outer leaflet of a Leishmania plasma membrane was used to decipher the HePC–lipid interactions.

Results: CH-OX, which is known to act more specifically on condensed membranes, therefore at the level of lipid rafts, gave a better extraction yield in HePC-resistant parasites, confirming the more rigid structure of their membranes than those of wild-type parasites. Sterol depletion was responsible for a 40% decrease in HePC susceptibility in both wild-type and HePC-resistant parasites. Sterol repletion of the sterol-depleted parasites restored HePC susceptibility. The biomimetic model of the outer leaflet of a Leishmania plasma membrane confirmed that condensed microdomains were able to incorporate higher quantities of HePC than fluid ones and this result was amplified when the sterol concentration was increased.

Conclusions: Sterol and lipid rafts probably play a significant role as an HePC reservoir providing a constant supply to the previously described transporter. In addition, 1H NMR experiments suggested that HePC stimulated lipid trafficking in parasites.

Keywords: antileishmanial action , chemotherapy , drug resistance , mechanism of action


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