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P-Glycoprotein-Like Transporters in Leishmania: A Search for Reversal Agents

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Drug Resistance in Leishmania Parasites

Abstract

Until now, chemotherapy has been the main line of defense against Leishmania infections. However, drug use and abuse have resulted in the selection and development of resistance mechanisms which strongly limit the number of antiprotozoal agents that are effective for the treatment of this disease. The emergence and spread of resistance to drugs currently in use and available for leishmaniasis emphasize that new compounds need to be identified and developed and that novel chemotherapeutic targets must be characterized. Mechanisms of drug resistance are often associated with decreased uptake of the drug into the parasite, poor drug activation, physiological alterations in the drug target, and overexpression of drug transporter proteins. One mechanism of resistance to antimony in Leishmania involves a decrease in its accumulation by either reduced uptake or increased efflux, mediated by P-glycoprotein (Pgp)-like transporters, which belong to the ATP-binding cassette (ABC) superfamily of proteins. The inhibition of the function of these proteins represents an attractive way to control drug resistance in clinical environments. New natural or synthetic sesquiterpenes, flavonoids, acridonecarboxamide derivative modulators of human Pgp (zosuquidar and elacridar), statins, pyridine analogs, 8-aminoquinolines, or phenothiazines revert in Leishmania the resistance phenotype to antimony, pentamidine, sodium stibogluconate, and miltefosine by modulating intracellular drug concentrations. In this chapter, we review some concepts concerning the reversal mechanism of multidrug resistance by the use chemosensitizers which alter the capacity of Pgp.

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  1. Unité Parasitologie et entomologie, Département des maladies infectieuses, Institut de Recherche Biomédicale des Armées, Marseille, France & Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, UM, Marseille, France

    Bruno Pradines

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  1. Institute of Experimental Medicine, Universidad Central de Venezuela, Caracas, Venezuela

    Alicia Ponte-Sucre

  2. Escuela Luis Razetti Fac de Medicine, Universidad Central de Venezuela, Caracas, Venezuela

    Maritza Padrón-Nieves

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Pradines, B. (2018). P-Glycoprotein-Like Transporters in Leishmania: A Search for Reversal Agents. In: Ponte-Sucre, A., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Cham. https://doi.org/10.1007/978-3-319-74186-4_14

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