The "pushmi-pullyu" of resistance to chloroquine in malaria

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 the Cinchona tree 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) and Plasmodium falciparum chloroquine-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.