title: Mechanisms of drug action and drug resistance in Leishmania as basis for therapeutic target identification and design of antileishmanial modulators.
abstract: The control of Leishmania infections relies primarily on chemotherapy. The arsenal of drugs available against Leishmania infections is limited and includes pentavalent antimonials, pentamidine, amphotericin B, miltefosine, paromomycin, allopurinol, and few other drugs at various stages of their development process. Knowledge about action and resistance mechanisms involved may allow the development of new drugs that minimise or circumvent drug resistance or may identify new targets for drug development. The aim of this review is to propose some chemical topics to design new modulators from the mechanisms of action of drugs and resistance mechanisms to drugs used in the clinic against Leishmania infections. Thus, different classes of ABC transporters extrude antimonials in Leishmania resulting in drug-resistant phenotypes. Compounds interfering with thiol and polyamine metabolism could be designed to inhibit the antimonial detoxication and therefore, such compounds could be used in combination with antimonials. New diamidines could be synthesized in regard to their ability to inhibit topoisomerase II. The challenge for amphotericin B is to be absorbed by oral route requiring labile physico-chemical modifications. New sesquiterpens and flavonoids have to be developed as reversant of antimonial resistance. Although some studies have focused on developing inhibitors against these resistant phenotypes, new efficient modulators that are able to inhibit drug efflux are needed.
authors.affiliation: Antiparasitic Chemotherapy Group, UMR 8076 CNRS, Faculty of Pharmacy, University of Paris South XI, 92290-Châtenay-Malabry, France. philippe.loiseau@cep.u-psud.fr
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Loiseau
authors.forename: Christian
authors.initials: C
authors.lastname: Bories
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015195:Drug Design; D004351:Drug Resistance; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000235:genetics; D007896:Leishmaniasis / Q000188:drug therapy*; D008968:Molecular Conformation; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018528:ATP-Binding Cassette Transporters; D000981:Antiprotozoal Agents; D005419:Flavonoids; D012717:Sesquiterpenes