| Alteration of fatty acid and sterol metabolism in miltefosine-resistant Leishmania donovani promastigotes and consequences for drug-membrane interactions. | |
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MedLine Citation:
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PMID: 15980336 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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M Rakotomanga; M Saint-Pierre-Chazalet; P M Loiseau |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: 49 ISSN: 0066-4804 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 2005 Jul |
Date Detail:
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Created Date: 2005-06-27 Completed Date: 2005-08-19 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: United States |
Other Details:
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Languages: eng Pagination: 2677-86 Citation Subset: IM |
Affiliation:
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Chimiothérapie Antiparasitaire, UMR 8076 CNRS, Faculté de Pharmacie, Université Paris XI, F-92290, Chātenay-Malabry, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antiprotozoal Agents / pharmacology*, therapeutic use Cell Membrane / drug effects, metabolism Drug Resistance* Fatty Acids / metabolism* Humans Leishmania donovani / drug effects*, growth & development Leishmaniasis, Visceral / drug therapy, parasitology Parasitic Sensitivity Tests Phosphorylcholine / analogs & derivatives*, pharmacology*, therapeutic use Sterols / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Antiprotozoal Agents; 0/Fatty Acids; 0/Sterols; 107-73-3/Phosphorylcholine; 58066-85-6/miltefosine |
| Comments/Corrections | |
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