This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pérez-Victoria, F. J.
Right arrow Articles by Gamarro, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pérez-Victoria, F. J.
Right arrow Articles by Gamarro, F.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2003, p. 2397-2403, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2397-2403.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Leishmania donovani Resistance to Miltefosine Involves a Defective Inward Translocation of the Drug

F. Javier Pérez-Victoria, Santiago Castanys, and Francisco Gamarro*

Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada, Spain

Received 10 February 2003/ Returned for modification 15 April 2003/ Accepted 2 May 2003

Miltefosine (hexadecylphosphocholine [HePC]) is the first drug approved for the oral treatment of visceral leishmaniasis. As part of a study on the mechanisms of action of this drug and on the rates of resistance to this drug, we have been working in vitro with an Leishmania donovani line that was previously shown to be 15-fold more resistant to HePC. We have studied the accumulation of [14C]HePC by L. donovani promastigotes and have found a drastic reduction (>95%) in the ability of the resistant line to internalize the drug. Binding of HePC to the plasma membrane and drug efflux from preloaded cells were similar in both drug-sensitive and -resistant lines, and no [14C]HePC metabolism was evident in either line. Resistant parasites were also unable to take up other short-chain phospholipid analogs, independently of their polar head group, even though endocytosis remained unaltered. Finally, HePC uptake was temperature and energy dependent and sensitive to the thiol-reactive agent N-ethylmaleimide. We propose that inward translocation of a short-chain phospholipid across the plasma membrane may exist in Leishmania promastigotes and that such activity is defective in the resistant line.

* Corresponding author. Mailing address: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, c/Ventanilla 11, 18001 Granada, Spain. Phone: 34-958-805185. Fax: 34-958-203911. E-mail: gamarro{at}ipb.csic.es.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2397-2403, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2397-2403.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sanchez-Canete, M. P., Carvalho, L., Perez-Victoria, F. J., Gamarro, F., Castanys, S. (2009). Low Plasma Membrane Expression of the Miltefosine Transport Complex Renders Leishmania braziliensis Refractory to the Drug. Antimicrob. Agents Chemother. 53: 1305-1313 [Abstract] [Full Text]  
  • Lopez-Martin, C., Perez-Victoria, J. M., Carvalho, L., Castanys, S., Gamarro, F. (2008). Sitamaquine Sensitivity in Leishmania Species Is Not Mediated by Drug Accumulation in Acidocalcisomes. Antimicrob. Agents Chemother. 52: 4030-4036 [Abstract] [Full Text]  
  • Castanys-Munoz, E., Perez-Victoria, J. M., Gamarro, F., Castanys, S. (2008). Characterization of an ABCG-Like Transporter from the Protozoan Parasite Leishmania with a Role in Drug Resistance and Transbilayer Lipid Movement. Antimicrob. Agents Chemother. 52: 3573-3579 [Abstract] [Full Text]  
  • McBride, J., Mullen, A. B., Carter, K. C., Roberts, C. W. (2007). Differential cytotoxicity of phospholipid analogues to pathogenic Acanthamoeba species and mammalian cells. J Antimicrob Chemother 60: 521-525 [Abstract] [Full Text]  
  • Coler, R. N., Goto, Y., Bogatzki, L., Raman, V., Reed, S. G. (2007). Leish-111f, a Recombinant Polyprotein Vaccine That Protects against Visceral Leishmaniasis by Elicitation of CD4+ T Cells. Infect. Immun. 75: 4648-4654 [Abstract] [Full Text]  
  • Dutta, A., Ghoshal, A., Mandal, D., Mondal, N. B., Banerjee, S., Sahu, N. P., Mandal, C. (2007). Racemoside A, an anti-leishmanial, water-soluble, natural steroidal saponin, induces programmed cell death in Leishmania donovani. J Med Microbiol 56: 1196-1204 [Abstract] [Full Text]  
  • Rakotomanga, M., Blanc, S., Gaudin, K., Chaminade, P., Loiseau, P. M. (2007). Miltefosine Affects Lipid Metabolism in Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 51: 1425-1430 [Abstract] [Full Text]  
  • Luque-Ortega, J. R., Rivas, L. (2007). Miltefosine (Hexadecylphosphocholine) Inhibits Cytochrome c Oxidase in Leishmania donovani Promastigotes. Antimicrob. Agents Chemother. 51: 1327-1332 [Abstract] [Full Text]  
  • Ashutosh, , Sundar, S., Goyal, N. (2007). Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56: 143-153 [Abstract] [Full Text]  
  • Perez-Victoria, J. M., Cortes-Selva, F., Parodi-Talice, A., Bavchvarov, B. I., Perez-Victoria, F. J., Munoz-Martinez, F., Maitrejean, M., Costi, M. P., Barron, D., Di Pietro, A., Castanys, S., Gamarro, F. (2006). Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux.. Antimicrob. Agents Chemother. 50: 3102-3110 [Abstract] [Full Text]  
  • Perez-Victoria, F. J., Sanchez-Canete, M. P., Castanys, S., Gamarro, F. (2006). Phospholipid Translocation and Miltefosine Potency Require Both L. donovani Miltefosine Transporter and the New Protein LdRos3 in Leishmania Parasites. J. Biol. Chem. 281: 23766-23775 [Abstract] [Full Text]  
  • Croft, S. L., Sundar, S., Fairlamb, A. H. (2006). Drug Resistance in Leishmaniasis. Clin. Microbiol. Rev. 19: 111-126 [Abstract] [Full Text]  
  • Rakotomanga, M., Saint-Pierre-Chazalet, M., Loiseau, P. M. (2005). Alteration of Fatty Acid and Sterol Metabolism in Miltefosine-Resistant Leishmania donovani Promastigotes and Consequences for Drug-Membrane Interactions. Antimicrob. Agents Chemother. 49: 2677-2686 [Abstract] [Full Text]  
  • Verma, N. K., Dey, C. S. (2004). Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani. Antimicrob. Agents Chemother. 48: 3010-3015 [Abstract] [Full Text]  
  • Perez-Victoria, F. J., Gamarro, F., Ouellette, M., Castanys, S. (2003). Functional Cloning of the Miltefosine Transporter: A NOVEL P-TYPE PHOSPHOLIPID TRANSLOCASE FROM LEISHMANIA INVOLVED IN DRUG RESISTANCE. J. Biol. Chem. 278: 49965-49971 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»