Malaria Journal：非洲疟原虫遗传突变显示出耐药性

在非洲致命性最强的疟原虫中，科学家已鉴定出遗传突变，这些突变使疟原虫能耐受最强效抗疟药，这表明最好的抗疟武器可能已过时。

青蒿素类药物是广泛应用的最有效的治疗疟疾药物，常与其他药物一起作为以青蒿素为基础的联合治疗（ACTs）使用，这时它最强效，几乎不可能被疟原虫耐受。但是，新研究则表明：疟原虫关键部分突变后能耐受青蒿素甲醚，其中青蒿素甲醚是2种最有效青蒿素中的一种。

在该研究中，研究人员从28位疟原虫感染病人中收集了11份疟原样品，经测试分析，这些样品都有青蒿素甲醚耐受性，青蒿素甲醚效果减半，每个样本疟原虫有相同遗传突变。说明疟原虫正在突变以发展耐药性，这正是大家所担心的。耐药性最终可能成为非洲的一个灾难怀问题，而不只是东南亚地区所留心的问题。在10位疟疾患者中，有9位死于恶性疟原虫感染，恶性疟原虫可引起致命性最强的疟疾，对青蒿素、青蒿素甲醚、二氢青蒿素和青蒿琥酯4种青蒿素敏感。经研究，发现11种耐受青蒿素甲醚疟原虫的内在钙泵系统存在相同遗传突变，钙泵用于转运钙离子，对疟原虫功能至关重要。在2003年时，研究人员不仅首次指出钙泵是青蒿素发挥作用的靶标，也怀疑钙泵有形成耐受青蒿素的潜力，但这个怀疑一直难以证实。

另外，还在几个病例中观察到青蒿素甲醚耐受最强的疟原虫，这些疟原虫中的另一个称为pfmdr1的转运系统有独立突变，也与耐药性有关。其他青蒿素的效果没有受该突变明显影响，这可能是因为这些青蒿素能作用于疟原虫的其他转运系统，弥补了钙泵的耐药性突变效应。耐药性可能是ACTs使用增加的结果，更大量的应用可能给疟原虫提供更多机会形成遗传突变。

目前，对于多数疟疾患者来说，有效替代治疗是负担不起的。因此，寻找新药物至关重要。（生物谷bioon.com）

doi:10.1186/1475-2875-11-131
PMC:
PMID:

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

Dylan R Pillai, Rachel Lau, Krishna Khairnar, Rosalba Lepore, Allegra Via, Henry M Staines, Sanjeev Krishna

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 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. 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.