Artemisinin Bioactivity and Resistance in Malaria Parasites

Artemisinin is the most widely-used compound against malaria and plays a critical role in the treatment of malaria worldwide. Resistance to artemisinin emerged about a decade ago in Southeast Asia and it is paramount to prevent its spread or emergence in Africa. Artemisinin has a complex mode of action and can cause widespread injury to many components of the parasite. In this review, we outline the different metabolic pathways affected by artemisinin, including the unfolded protein response, protein polyubiquitination, proteasome, phosphatidylinositol-3-kinase, and the eukaryotic translation initiation factor 2 alpha. Based on recently published data, we present a model of how these different pathways interplay and how mutations in K13, the main identified resistance marker, may help parasites survive under artemisinin pressure.