Drug resistance in Plasmodium

Resistance to frontline artemisinins and partner drugs is now causing the failure of artemisinin-based combination therapies against Plasmodium falciparum in southeast Asia.Triple artemisinin-based combination therapies are being developed, but their design and deployment require an understanding of background resistance and associated genetic mutations of the parasite populations being targeted.P. falciparum Kelch 13 (PfKelch13), the marker for artemisinin resistance in P. falciparum malaria, is not an enzyme or a pump but rather is predicted to be a substrate adapter for a cullin E3 ligase, with a putative substrate of P. falciparum phosphatidylinositol 3-kinase (PfPI3K) and a redox sensor.Mutation in pfkelch13 appears to increase parasite phosphatidylinositol-3-phosphate (PtdIns3P) as well as the unfolded protein response, and both have been proposed as mechanisms of artemisinin resistance.Additional PfKelch13-independent mechanisms of artemisinin resistance have appeared in southeast Asia.The identification of mechanisms of resistance to artemisinin and its partner drugs as well as of new targets for chemotherapy that can eliminate resistant infection in both symptomatic and asymptomatic populations is needed for malaria elimination.