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Antimicrobial Agents and Chemotherapy, February 2001, p. 439-446, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.439-446.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

High-Affinity Binding of Silybin Derivatives to the Nucleotide-Binding Domain of a Leishmania tropica P-Glycoprotein-Like Transporter and Chemosensitization of a Multidrug-Resistant Parasite to Daunomycin

José M. Pérez-Victoria,1 F. Javier Pérez-Victoria,1 Gwenaëlle Conseil,2 Mathias Maitrejean,3 Gilles Comte,3 Denis Barron,3 Attilio Di Pietro,2 Santiago Castanys,1 and Francisco Gamarro1,*

Instituto de Parasitologia y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Científicas, Granada, Spain,1 and Institut de Biologie et Chimie des Protéines, UPR 412 du CNRS, Lyon,2 and Laboratoire des Produits Naturels, UMR-CNRS 5013, Université Claude Bernard de Lyon, Villeurbanne,3 France

Received 25 May 2000/Returned for modification 5 September 2000/Accepted 8 November 2000

In order to overcome the multidrug resistance mediated by P-glycoprotein-like transporters in Leishmania spp., we have studied the effects produced by derivatives of the flavanolignan silybin and related compounds lacking the monolignol unit on (i) the affinity of binding to a recombinant C-terminal nucleotide-binding domain of the L. tropica P-glycoprotein-like transporter and (ii) the sensitization to daunomycin on promastigote forms of a multidrug-resistant L. tropica line overexpressing the transporter. Oxidation of the flavanonol silybin to the corresponding flavonol dehydrosilybin, the presence of the monolignol unit, and the addition of a hydrophobic substituent such as dimethylallyl, especially at position 8 of ring A, considerably increased the binding affinity. The in vitro binding affinity of these compounds for the recombinant cytosolic domain correlated with their modulation of drug resistance phenotype. In particular, 8-(3,3-dimethylallyl)-dehydrosilybin effectively sensitized multidrug-resistant Leishmania spp. to daunomycin. The cytosolic domains are therefore attractive targets for the rational design of inhibitors against P-glycoprotein-like transporters.

* Corresponding author. Mailing address: Instituto de Parasitologia y Biomedicina "López-Neyra," Consejo Superior de Investigaciones Cientificas, 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, February 2001, p. 439-446, Vol. 45, No. 2
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.2.439-446.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • 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, J. M., Perez-Victoria, F. J., Parodi-Talice, A., Jimenez, I. A., Ravelo, A. G., Castanys, S., Gamarro, F. (2001). Alkyl-Lysophospholipid Resistance in Multidrug-Resistant Leishmania tropica and Chemosensitization by a Novel P-Glycoprotein-Like Transporter Modulator. Antimicrob. Agents Chemother. 45: 2468-2474 [Abstract] [Full Text]  


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