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Antimicrobial Agents and Chemotherapy, September 2001, p. 2468-2474, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2468-2474.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Alkyl-Lysophospholipid Resistance in Multidrug-Resistant Leishmania tropica and Chemosensitization by a Novel P-Glycoprotein-Like Transporter Modulator

José M. Pérez-Victoria,1 F. Javier Pérez-Victoria,1 Adriana Parodi-Talice,1 Ignacio A. Jiménez,2 Angel G. Ravelo,2 Santiago Castanys,1 and Francisco Gamarro1,*

Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada,1 and Instituto Universitario de Bio-Orgánica "Antonio González," Universidad de La Laguna, La Laguna, Tenerife,2 Spain

Received 27 February 2001/Returned for modification 12 April 2001/Accepted 5 June 2001

Drug resistance has emerged as a major impediment in the treatment of leishmaniasis. Alkyl-lysophospholipids (ALP), originally developed as anticancer drugs, are considered to be the most promising antileishmanial agents. In order to anticipate probable clinical failure in the near future, we have investigated possible mechanisms of resistance to these drugs in Leishmania spp. The results presented here support the involvement of a member of the ATP-binding cassette (ABC) superfamily, the Leishmania P-glycoprotein-like transporter, in the resistance to ALP. (i) First, a multidrug resistance (MDR) Leishmania tropica line overexpressing a P-glycoprotein-like transporter displays significant cross-resistance to the ALP miltefosine and edelfosine, with resistant indices of 9.2- and 7.1-fold, respectively. (ii) Reduced expression of P-glycoprotein in the MDR line correlates with a significant decrease in ALP resistance. (iii) The ALP were able to modulate the P-glycoprotein-mediated resistance to daunomycin in the MDR line. (iv) We have found a new inhibitor of this transporter, the sesquiterpene C-3, that completely sensitizes MDR parasites to ALP. (v) Finally, the MDR line exhibits a lower accumulation than the wild-type line of bodipy-C5-PC, a fluorescent analogue of phosphatidylcholine that has a structure resembling that of edelfosine. Also, C-3 significantly increases the accumulation of the fluorescent analogue to levels similar to those of wild-type parasites. The involvement of the Leishmania P-glycoprotein-like transporter in resistance to drugs used in the treatment of leishmaniasis also supports the importance of developing new specific inhibitors of this ABC transporter.

* 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: 34-958-203323. E-mail: gamarro{at}ipb.csic.es.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2468-2474, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2468-2474.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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