The drugs chloroquine and piperaquine have followed the well-known and chemically related quinine as treatments for malaria. However, resistance to both drugs has emerged in Asia, and more recently piperaquine resistance has become widespread in Southeast Asia. Although it is known that the main determinant of resistance is the transporter PfCRT, the mechanisms of resistance are unknown. Here, Filippo Mancia and colleagues report the structure of the 7G8 transporter variant that is chloroquine resistant but sensitive to piperaquine. In combination with functional and genetic studies of a series of transporter variants, this work provides key insights into the complex resistance mechanisms of PfCRT. It provides a framework by which to study emerging resistance mechanisms to stay one step ahead of the parasite.
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