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Antimicrobial Agents and Chemotherapy, September 2006, p. 3102-3110, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00423-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

José M. Pérez-Victoria,1 Fernando Cortés-Selva,1 Adriana Parodi-Talice,1,{dagger} Boris I. Bavchvarov,1,{ddagger} F. Javier Pérez-Victoria,1 Francisco Muñoz-Martínez,1 Mathias Maitrejean,2 M. Paola Costi,3 Denis Barron,2 Attilio Di Pietro,4 Santiago Castanys,1,§ and Francisco Gamarro1,§*

Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada, Spain,1 Laboratoire des Produits Naturels, UMR 5013 CNRS/Université Claude Bernard-Lyon I, Villeurbanne, France,2 Dipartimento di Scienze Farmaceutiche, Universit á degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy,3 Institut de Biologie et Chimie des Protéines, UMR 5086 CNRS/Université de Lyon, IFR 128 BioSciences Lyon-Gerland, 7 Passage du Vercors, 69637 Lyon Cedex 07, France4

Received 5 April 2006/ Returned for modification 3 May 2006/ Accepted 27 June 2006

Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-ß-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

* Corresponding author. Mailing address: Instituto de Parasitología y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100-Armilla, Granada, Spain. Phone: 34958181667. Fax: 34958181632. E-mail: gamarro{at}ipb.csic.es.

{dagger} Present address: Sección Genética/Facultad de Ciencias, Montevideo, Uruguay.

{ddagger} Present address: Institute of Molecular Biology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.

§ S.C. and F.G. are equal senior investigators in this study.

Antimicrobial Agents and Chemotherapy, September 2006, p. 3102-3110, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00423-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • 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]  


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