Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections.
Artemether resistance in vitro is linked to mutations in PfATP6 that also interact with mutations in PfMDR1 in travellers returning with Plasmodium falciparum infections.
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DOI：
10.1186/1475-2875-11-131
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发表时间：
2012-04-27
期刊：
影响因子：
3
通讯作者：
Krishna S
中科院分区：
文献类型：
--
作者：
Pillai DR;Lau R;Khairnar K;Lepore R;Via A;Staines HM;Krishna S
使用体外生长测定法监测恶性疟原虫的抗药性表型，并将结果与寄生虫基因型联系起来，这对青蒿素抗药性研究来说尤其具有挑战性。从28名被诊断为疟疾的回国旅行者中培养的恶性疟原虫分离株对青蒿素、蒿甲醚、双氢青蒿素和青蒿琥酯的敏感性以及与pfatp 6和pfmdr 1突变相关的发现进行了评估。体外对蒿甲醚的抗性与编码两个氨基酸取代的pfatp 6单倍型显著相关（pfatp 6 A623 E和S769 N;（平均IC 50（95%CI）值为8.2（5.7 - 10.7）相比623 E/769 N 13.5（9.8 - 17.3）nM，平均增加65%; p = 0.012）。pfmdr 1拷贝数的增加本身与蒿甲醚IC 50值的增加无关，但当pfatp 6单倍型和pfmdr 1拷贝数增加之间的相互作用一起检查时，注意到蒿甲醚的IC 50值与（平均IC 50（95% CI）值为8.7（5.9 - 11.6）vs 16.3（10.7 - 21.8）nM，平均增加87%; p = 0.0068）。先前描述的pfmdr 1中的SNP也与对某些青蒿素的敏感性差异相关。这些发现在分子模拟实验中得到了进一步的探索，表明pfatp 6的突变不太可能影响青蒿素在其拟议位点的差异结合，而这种结合可能与pfmdr 1的突变有关。青蒿素耐药性可能加剧PfATP 6和PfMDR 1之间的相互作用和流行病学研究，以监测新出现的耐药性的假设的影响进行了讨论。
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. 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. Resistance to artemether in vitro was significantly associated with a pfatp6 haplotype encoding two amino acid substitutions (pfatp6 A623E and S769N; (mean IC50 (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 IC50 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 IC50 values for artemether (mean IC50 (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. 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.
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影响因子：
3
作者：
Lim P;Alker AP;Khim N;Shah NK;Incardona S;Doung S;Yi P;Bouth DM;Bouchier C;Puijalon OM;Meshnick SR;Wongsrichanalai C;Fandeur T;Le Bras J;Ringwald P;Ariey F
通讯作者：
Ariey F
影响因子：
3.7
作者：
Ferreira PE;Holmgren G;Veiga MI;Uhlén P;Kaneko A;Gil JP
通讯作者：
Gil JP
影响因子：
4.9
作者：
Legrand, Eric;Volney, Beatrice;Esterre, Philippe
通讯作者：
Esterre, Philippe
影响因子：
1.5
作者：
Duraisingh, MT;Jones, P;Warhurst, DC
通讯作者：
Warhurst, DC
DOI：
10.1073/pnas.91.3.1143
发表时间：
1994-02-01
影响因子：
11.1
作者：
COWMAN, AF;GALATIS, D;THOMPSON, JK
通讯作者：
THOMPSON, JK