Plasmodium falciparum Artemisinin Resistance: The Effect of Heme, Protein Damage, and Parasite Cell Stress Response.
Plasmodium falciparum Artemisinin Resistance: The Effect of Heme, Protein Damage, and Parasite Cell Stress Response.
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DOI：
10.1021/acsinfecdis.9b00527
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发表时间：
2020-07-10
影响因子：
5.3
通讯作者：
Ng CL
中科院分区：
文献类型：
--
作者：
Rosenthal MR;Ng CL
尽管在过去二十年中发病率和死亡率显著下降，但2018年仍有2.28亿例疟疾报告病例和40.5万例疟疾相关死亡。青蒿素是以青蒿素为基础的综合疗法的基石，也是抗恶性疟疾抗疟药物中最有效的药物。血红素介导的青蒿素及其衍生物的活化导致广泛的寄生虫蛋白质烷基化，这被认为导致寄生虫死亡。令人震惊的是，柬埔寨和邻国广泛发现青蒿素疗效下降的病例，圭亚那盾、印度和非洲也报告了少数病例。广泛存在的青蒿素耐药性的严峻前景促使人们共同努力了解青蒿素作用和耐药性的机制。遗传标记的识别和对青蒿素耐药性分子机制的了解分别可以进行前瞻性监测并为未来的药物开发策略提供信息。在这里，我们强调了最近的进展，我们的理解如何寄生虫囊泡运输，血红蛋白消化，细胞应激反应有助于青蒿素耐药性。血红素介导的青蒿素活化对疟原虫寄生虫造成广泛损害。虽然抗性的确切机制尚未完全阐明，但抗性可能是由可用游离血红素的减少和/或寄生虫应激反应能力的增加介导的。在这里，我们回顾了寄生虫遗传学对青蒿素耐药性的贡献，以及这些基因（包括K13）如何介导青蒿素耐药性。
Despite a significant decline in morbidity and mortality over the last two decades, in 2018 there were 228 million reported cases of malaria and 405,000 malaria-related deaths. Artemisinin, the cornerstone of artemisinin-based combination therapies, is the most potent drug in the antimalarial armamentarium against falciparum malaria. Heme-mediated activation of artemisinin and its derivatives results in widespread parasite protein alkylation, which is thought to lead to parasite death. Alarmingly, cases of decreased artemisinin efficacy have been widely detected across Cambodia and in neighboring countries, and a few cases have been reported in the Guiana Shield, India, and Africa. The grim prospect of widespread artemisinin resistance propelled a concerted effort to understand the mechanisms of artemisinin action and resistance. Identification of genetic markers and knowledge of molecular mechanisms underpinning artemisinin resistance allow prospective surveillance and inform future drug development strategies, respectively. Here, we highlight recent advances in our understanding of how parasite vesicle trafficking, hemoglobin digestion, and cell stress responses contribute to artemisinin resistance. Heme-mediated activation of artemisinins causes widespread damage to Plasmodium parasites. Though the exact mechanism of resistance has not been fully elucidated, resistance may be mediated by a decrease in available free heme and/or an increased parasite stress response capacity. Here, we review the contribution of parasite genetics to artemisinin resistance and how these genes, including K13, may mediate artemisinin resistance.
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与柬埔寨恶性疟原虫疟疾双氢青蒿素-哌喹失败相关的遗传标记：基因型-表型关联研究。
DOI：
10.1016/s1473-3099(16)30409-1
发表时间：
2017-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
Amato R;Lim P;Miotto O;Amaratunga C;Dek D;Pearson RD;Almagro-Garcia J;Neal AT;Sreng S;Suon S;Drury E;Jyothi D;Stalker J;Kwiatkowski DP;Fairhurst RM
通讯作者：
Fairhurst RM
影响因子：
4.6
作者：
Borrmann S;Straimer J;Mwai L;Abdi A;Rippert A;Okombo J;Muriithi S;Sasi P;Kortok MM;Lowe B;Campino S;Assefa S;Auburn S;Manske M;Maslen G;Peshu N;Kwiatkowski DP;Marsh K;Nzila A;Clark TG
通讯作者：
Clark TG
影响因子：
12.3
作者：
Cerqueira GC;Cheeseman IH;Schaffner SF;Nair S;McDew-White M;Phyo AP;Ashley EA;Melnikov A;Rogov P;Birren BW;Nosten F;Anderson TJC;Neafsey DE
通讯作者：
Neafsey DE
影响因子：
5.3
作者：
Cullinan, SB;Gordan, JD;Diehl, JA
通讯作者：
Diehl, JA
影响因子：
4.9
作者：
Afonso, A;Hunt, P;Cravo, P
通讯作者：
Cravo, P