Function of Resistance Conferring Plasmodium falciparum Chloroquine Resistance Transporter Isoforms

The function of Plasmodium falciparum chloroquine resistance transporter (PfCRT) can be quantified using a Saccharomyces cerevisiae model system [Baro, N. K., Pooput, C., and Roepe, P. D. (2011) Biochemistry 50, 6701-6710]. We further optimized this system to distinguish PfCRT isoforms found in P. falciparum strains and isolates from across the globe. We created and expressed 13 naturally occurring pfcrt alleles associated with a range of chloroquine resistant (CQR) phenotypes. Using galactose induction of PfCRT, we quantified PfCRT and chloroquine (CQ)-dependent yeast growth inhibition and [H-3]CQ transport specifically due to a given PfCRT isoform. Surprisingly, we found poor correlation between these parameters and the CQ IC50 observed in strains of malaria harboring the same isoforms. This suggested that an increased level of CQ transport due to PfCRT mutation is necessary, but not sufficient, for the range of CQ IC50 values observed in globally distributed CQR P. falciparum isolates.