Lack of association of the S769N mutation in Plasmodium falciparum SERCA (PfATP6) with resistance to artemisinins.

The recent emergence of artemisinin (ART) resistance in Plasmodium falciparum in western Cambodia, manifested as delayed parasite clearance, is a big threat to the long-term efficacy of this family of antimalarial drugs. Among the multiple candidate genes associated with ART resistance in P. falciparum, the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase PfATP6 has been postulated as a specific target of ARTs. The PfATP6 gene harbors multiple single-nucleotide polymorphisms in field parasite populations, and S769N has been associated with decreased sensitivity to artemether in parasite populations from French Guiana. In this study, we used an allelic exchange strategy to engineer parasite lines carrying the S769N mutations in P. falciparum strain 3D7 and evaluated whether introduction of this mutation modulated parasite sensitivity to ART derivatives. Using three transgenic lines carrying the 769N mutation and two transgenic lines carrying the wild-type 769S as controls, we found that S769N did not affect PfATP6 gene expression. We compared the sensitivities of these parasite lines to three ART derivatives, artemether, artesunate, and dihydroartemisinin, in 18 biological experiments and detected no significant effect of the S769N mutation on parasite response to these ART derivatives. This study provides further evidence for the lack of association of PfATP6 with ART resistance.