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Antimicrobial Agents and Chemotherapy, July 2005, p. 2677-2686, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2677-2686.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Alteration of Fatty Acid and Sterol Metabolism in Miltefosine-Resistant Leishmania donovani Promastigotes and Consequences for Drug-Membrane Interactions

M. Rakotomanga,1 M. Saint-Pierre-Chazalet,1,2 and P. M. Loiseau1*

Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris XI, F-92290 Chatenay-Malabry, France,1 Laboratoire de Physicochimie Biomoléculaire et Cellulaire, UMR 7033 CNRS, Université Pierre et Marie Curie-Paris VI, 75252 Paris, France2

Received 20 September 2004/ Returned for modification 16 November 2004/ Accepted 28 February 2005

Miltefosine (hexadecylphosphocholine [HePC]) is the first orally active drug approved for the treatment of visceral leishmaniasis. In order to investigate the biochemical modifications occurring in HePC-resistant (HePC-R) Leishmania donovani promastigotes, taking into account the lipid nature of HePC, we investigated their fatty acid and sterol metabolisms. We found that the content of unsaturated phospholipid alkyl chains was lower in HePC-R parasite plasma membranes than in those of the wild type, suggesting a lower fluidity of HePC-R parasite membranes. We also demonstrated that HePC insertion within an external monolayer was more difficult when the proportion of unsaturated phospholipids decreased, rendering the HePC interaction with the external monolayer of HePC-R parasites more difficult. Furthermore, HePC-R parasite membranes displayed a higher content of short alkyl chain fatty acids, suggesting a partial inactivation of the fatty acid elongation enzyme system in HePC-R parasites. Sterol biosynthesis was found to be modified in HePC-R parasites, since the 24-alkylated sterol content was halved in HePC-R parasites; however, this modification was not related to HePC sensitivity. In conclusion, HePC resistance affects three lipid biochemical pathways: fatty acid elongation, the desaturase system responsible for fatty acid alkyl chain unsaturation, and the C-24-alkylation of sterols.

* Corresponding author. Mailing address: Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris XI, F-92290, Chatenay-Malabry, France. Phone: 33-1 46 83 55 53. Fax: 33-1 46 83 55 57. E-mail: Philippe.Loiseau{at}cep.u-psud.fr.

Antimicrobial Agents and Chemotherapy, July 2005, p. 2677-2686, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2677-2686.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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