Modeling mutant PfCRT-mediated drug transport to predict the emergence of piperaquine-resistant Plasmodium falciparum malaria

PROJECT NARRATIVE Global efforts to control and eventually eliminate Plasmodium falciparum malaria have been thwarted by the emergence of resistance to first-line antimalarials, including piperaquine (PPQ) in Southeast Asia, mediated by the drug efflux transporter PfCRT. This project combines in vitro transport studies to understand the mechanism of PfCRT-mediated transport of PPQ and other substrates, and genetic engineering of PPQ-resistant mutations onto African and South American PfCRT haplotypes in P. falciparum parasites in order to predict how PPQ resistance could spread to or emerge in these regions and thereby compromise malaria treatment and control. Our findings will provide important insights into the molecular basis of antimalarial drug resistance, which is of direct relevance to the goal of reducing the morbidity, mortality, and socioeconomic burden of malaria.