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Background  Monitoring resistance phenotypes for  Plasmodium falciparum , using  in vitro  growth assays, and relating findings to parasite genotype has proved particularly challenging for the study of resistance to artemisinins.    Methods   Plasmodium falciparum  isolates cultured from 28 returning travellers diagnosed with malaria were assessed for sensitivity to artemisinin, artemether, dihydroartemisinin and artesunate and findings related to mutations in  pfatp6  and  pfmdr1 .    Results  Resistance to artemether  in vitro  was significantly associated with a  pfatp6  haplotype encoding two amino acid substitutions ( pfatp6  A623E and S769N; (mean IC 50  (95% CI) values of 8.2 (5.7 – 10.7) for A623/S769  versus  623E/769 N 13.5 (9.8 – 17.3) nM with a mean increase of 65%; p = 0.012). Increased copy number of  pfmdr1  was not itself associated with increased IC 50  values for artemether, but when interactions between the  pfatp6  haplotype and increased copy number of  pfmdr1  were examined together, a highly significant association was noted with IC 50  values for artemether (mean IC 50  (95% CI) values of 8.7 (5.9 – 11.6)  versus  16.3 (10.7 – 21.8) nM with a mean increase of 87%; p = 0.0068). Previously described SNPs in  pfmdr1  are also associated with differences in sensitivity to some artemisinins.    Conclusions  These findings were further explored in molecular modelling experiments that suggest mutations in  pfatp6  are unlikely to affect differential binding of artemisinins at their proposed site, whereas there may be differences in such binding associated with mutations in  pfmdr1 . Implications for a hypothesis that artemisinin resistance may be exacerbated by interactions between PfATP6 and PfMDR1 and for epidemiological studies to monitor emerging resistance are discussed.

malaria journal

Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections