Mechanism of interaction of sitamaquine with Leishmania donovani
| Autor: | Sandrine Cojean, A. M. Duenas-Romero, L. Le Moyec, D. Libong, Elaine Soares Coimbra, Pierre Chaminade, Audrey Solgadi, M. Saint-Pierre-Chazalet, Philippe M. Loiseau |
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| Rok vydání: | 2010 |
| Předmět: |
Microbiology (medical)
Antiprotozoal Agents Phospholipid Leishmania donovani Diffusion Cell membrane Membrane Lipids chemistry.chemical_compound Biomimetic Materials parasitic diseases medicine Animals Pharmacology (medical) Phospholipids Pharmacology biology Membrane transport protein Cell Membrane Biological membrane Leishmania biology.organism_classification Sterols Cytosol Infectious Diseases medicine.anatomical_structure chemistry Biochemistry Aminoquinolines biology.protein lipids (amino acids peptides and proteins) Efflux |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 65:2548-2555 |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dkq371 |
| Popis: | Objectives: This study focuses on the mechanism of interaction of sitamaquine with Leishmania donovani membranes, and its accumulation within the parasites. Methods: A biomimetic model of the outer layer of a Leishmania plasma membrane was used to examine the interactions of sitamaquine with lipids. The plasma membranes of L. donovani promastigotes were depleted of sterol using cholesterol oxidase, in order to assess the importance of sterols in drug-membrane interactions. Sterols were quantified and sitamaquine susceptibility was assessed using the MTT test. Kinetics of sitamaquine accumulation and efflux were measured under different conditions. Results: Sitamaquine interacts first with phospholipid anionic polar head groups and then with phospholipid acyl chains to insert within biological membranes and accumulates rapidly in the Leishmania cytosol according to a sterol-independent process. The rapid sitamaquine efflux observed was related to an energy-dependent mechanism since the intracellular amount of sitamaquine was enhanced three times in the absence of glucose and the efflux was inhibited in energy-depleted conditions. 1 H NMR analysis of motile lipid showed that sitamaquine did not affect lipid trafficking in Leishmania. Conclusions: We propose that sitamaquine rapidly accumulates in Leishmania by diffusion along an electrical gradient and is concentrated in the cytosol by an energy- and sterol-independent process. The affinity of sitamaquine for membranes was transitory and an energy-dependent efflux was demonstrated, suggesting the presence of an as yet uncharacterized transporter. |
| Databáze: | OpenAIRE |
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