Chemosensitizers in drug transport mechanisms involved in protozoan resistance.
The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the P-glycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.
Unité de Recherche en Biologie et Epidemiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France.
Bruno
B
Pradines
Jean-Marie
JM
Pagès
Jacques
J
Barbe
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D007891:Leishmania / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010961:Plasmodium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins; D014345:Trypanosoma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000929:Antidepressive Agents, Tricyclic; D000981:Antiprotozoal Agents; D002121:Calcium Channel Blockers; D006634:Histamine H1 Antagonists; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C416369:PfCRT protein, Plasmodium falciparum