title: The "pushmi-pullyu" of resistance to chloroquine in malaria.
abstract: Malarial infection continues to impart devastating health problems in the developing world. Treatment of malaria has involved chemotherapy since 168 BC, with the most prevalent and successful forms using plant alkaloids. Perhaps the greatest treatment success against malaria was by chloroquine, a synthetic derivative of the quinines found in theCinchonatree bark. Chloroquine is able to kill parasites by interfering with haem metabolism in the parasite's digestive vacuole. The widespread use of chloroquine predictably resulted in the development of drug-resistant malaria and the most highly implicated resistance mediators are the transporter proteins P-glycoprotein (P-gp) homologue 1 (P-gh1) andPlasmodium falciparumchloroquine-resistance transporter (PfCRT), which reside on the parasite's digestive vacuole. The presence of PfCRT and P-gh1 on the vacuole membrane is analogous to the two-headed fictional creature known as the "Pushmi-Pullyu". P-gh1 (Pushmi) increases influx of chloroquine into the vacuole, while PfCRT (Pullmi) causes efflux of chloroquine from the vacuole. This review describes how drug-resistant malarial parasites co-ordinate chloroquine distribution through adaptive mutations to promote their survival in the presence of this cytotoxic drug.
authors.affiliation: Division of Biomedical Sciences and Biochemistry, Research School of Biology and Medical School, Australian National University, Canberra, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Skrzypek
authors.affiliation: Division of Biomedical Sciences and Biochemistry, Research School of Biology and Medical School, Australian National University, Canberra, Australia richard.callaghan@anu.edu.au.
authors.forename: Richard
authors.initials: R
authors.lastname: Callaghan
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use*; D004351:Drug Resistance / Q000187:drug effects*; D049673:History, 20th Century; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000266:history; D026901:Membrane Transport Proteins / Q000378:metabolism; D010271:Parasites / Q000187:drug effects / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine
keywords: ABC transport proteins; PfCRT; chloroquine; malaria resistance; pfMDR