Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine

• DOI: 10.1038/s41467-018-05652-0
• Publication Date: 2018-08-13T15:35:42Z
• Authors: Leila S. Ross; Satish K. Dhingra; Sachel Mok; Tomas Yeo; Kathryn J. Wicht; Krittikorn Kümpor...; Shannon Takala-Ha...; Benoit Witkowski; Rick M. Fairhurst; Frederic Ariey; Didier Menard; David A. Fidock
• Keywords: Science; Plasmodium falciparum; Drug Resistance; Gene Dosage; Protozoan Proteins; Article; Antimalarials; 03 medical and health sciences; Animals; Humans; [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology; Parasites; Malaria, Falciparum; Cell Shape; Gene Editing; 0303 health sciences; Q; Membrane Transport Proteins; Chloroquine; 3. Good health; Haplotypes; Verapamil; Mutation; Quinolines; Cambodia; [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology

AbstractThe widely used antimalarial combination therapy dihydroartemisinin + piperaquine (DHA + PPQ) has failed in Cambodia. Here, we perform a genomic analysis that reveals a rapid increase in the prevalence of novel mutations in the Plasmodium falciparum chloroquine resistance transporter PfCRT following DHA + PPQ implementation. These mutations occur in parasites harboring the K13 C580Y artemisinin resistance marker. By introducing PfCRT mutations into sensitive Dd2 parasites or removing them from resistant Cambodian isolates, we show that the H97Y, F145I, M343L, or G353V mutations each confer resistance to PPQ, albeit with fitness costs for all but M343L. These mutations sensitize Dd2 parasites to chloroquine, amodiaquine, and quinine. In Dd2 parasites, multicopy plasmepsin 2, a candidate molecular marker, is not necessary for PPQ resistance. Distended digestive vacuoles were observed in pfcrt-edited Dd2 parasites but not in Cambodian isolates. Our findings provide compelling evidence that emerging mutations in PfCRT can serve as a molecular marker and mediator of PPQ resistance.