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Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine
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Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine
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Journal Article
Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine
2018
Overview
The 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.
Increasing resistance of
Plasmodium falciparum
strains to piperaquine (PPQ) in Southeast Asia is of concern and resistance mechanisms are incompletely understood. Here, Ross et al. show that mutations in the
P
.
falciparum
chloroquine resistance transporter are rapidly increasing in prevalence in Cambodia and confer resistance to PPQ.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 45/23
/ 45/41
/ 45/77
/ Animals
/ Antimalarials - pharmacology
/ Antimalarials - therapeutic use
/ Cambodia
/ Chloroquine - therapeutic use
/ Drug Resistance - drug effects
/ Fitness
/ Humanities and Social Sciences
/ Humans
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - parasitology
/ Membrane Transport Proteins - genetics
/ Microbiology and Parasitology
/ Mutation
/ Parasites - growth & development
/ Plasmodium falciparum - drug effects
/ Plasmodium falciparum - genetics
/ Plasmodium falciparum - growth & development
/ Plasmodium falciparum - isolation & purification
/ Protozoan Proteins - genetics
/ Quinine
/ Quinolines - therapeutic use
/ Science
/ Vacuoles
