Functional characteristics of the malaria parasite's 'chloroquine resistance transporter' implications for chemotherapy

Abstract

Chloroquine (CQ) was the best and most heavily used drug in the fight against malaria. However, the effectiveness of CQ has declined with the emergence and spread of CQ-resistant (CQR) Plasmodium falciparum parasites. The primary determinant of CQ resistance in P. falciparum is mutations in the parasite's 'chloroquine resistance transporter' (PfCRT). These mutations result in a marked reduction in the accumulation of CQ by the parasite; however the mechanism by which this is achieved was not understood. We have recently shown that the mutations confer upon PfCRT the ability to transport CQ away from its site of accumulation and action. Sensitive and resistance-conferring forms of the protein (PfCRTCQS and PfCRTCQR, respectively) were expressed at the surface of Xenopus laevis oocytes, and it was found that PfCRTCQR (but not PfCRTCQS) transports CQ. Here we discuss and expand upon our findings to address the question of whether PfCRTCQR behaves as a carrier or a channel, and how this distinction has significant implications for the treatment of CQR P. falciparum with CQ or CQ-like drugs. In particular we relate this to the example of Guinea- Bissau, where high doses of CQ are routinely used to treat CQR P. falciparum malaria.