Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.
Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.
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DOI：
10.1016/j.ijpddr.2021.05.007
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Cui L
中科院分区：
文献类型：
--
作者：
Siddiqui FA;Liang X;Cui L
在东南亚多药耐药性中心，恶性疟原虫对一线治疗青蒿素类联合疗法的耐药性的出现和蔓延威胁着全球疟疾控制和消除。青蒿素（ART）耐药性（或耐受性）在临床上被定义为用ART药物治疗后延迟的寄生虫清除。抗性表型仅限于早期年轮阶段，并且可以使用年轮阶段存活测定法在体外测量。ART抗性与Kelch家族蛋白K13的螺旋桨结构域中的突变相关。作为前药，ART主要由血红素激活，血红素主要来源于食物泡中的血红蛋白消化。活化的ART可以与广泛的细胞靶点发生混杂反应，破坏细胞蛋白质稳态。与ART的这种作用模式一致，K13介导的ART抗性的分子机制涉及血红蛋白摄取/消化减少和细胞应激反应增加。其他基因的突变，如AP-2μ（衔接蛋白-2 μ亚基），UBP-1（泛素结合蛋白-1）和Falcipain 2a，干扰血红蛋白的摄取和消化，也增加了对ART的抵抗力。抗逆转录病毒疗法耐药性促进了对伙伴药物耐药性的发展，导致ACT疗效迅速下降。对合作伙伴药物的耐药性的分子标志物主要与两种食物液泡膜转运蛋白PfCRT和PfMDR 1的点突变以及PfMDR 1和两种天冬氨酸蛋白酶基因plasmepsin 2和3的扩增相关。据观察，这些基因的突变可能对不同伴侣药物的敏感性产生相反的影响，这是设计三联ACT和药物轮换的原则。尽管ACT临床耐药性仅限于东南亚，但需要使用体内临床疗效、体外测定和分子方法监测耐药性，以预防或减缓耐药寄生虫的传播。
Emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies (ACTs) in the epicenter of multidrug resistance of Southeast Asia threaten global malaria control and elimination. Artemisinin (ART) resistance (or tolerance) is defined clinically as delayed parasite clearance after treatment with an ART drug. The resistance phenotype is restricted to the early ring stage and can be measured in vitro using a ring-stage survival assay. ART resistance is associated with mutations in the propeller domain of the Kelch family protein K13. As a pro-drug, ART is activated primarily by heme, which is mainly derived from hemoglobin digestion in the food vacuole. Activated ARTs can react promiscuously with a wide range of cellular targets, disrupting cellular protein homeostasis. Consistent with this mode of action for ARTs, the molecular mechanisms of K13-mediated ART resistance involve reduced hemoglobin uptake/digestion and increased cellular stress response. Mutations in other genes such as AP-2μ (adaptor protein-2 μ subunit), UBP-1 (ubiquitin-binding protein-1), and Falcipain 2a that interfere with hemoglobin uptake and digestion also increase resistance to ARTs. ART resistance has facilitated the development of resistance to the partner drugs, resulting in rapidly declining ACT efficacies. The molecular markers for resistance to the partner drugs are mostly associated with point mutations in the two food vacuole membrane transporters PfCRT and PfMDR1, and amplification of pfmdr1 and the two aspartic protease genes plasmepsin 2 and 3. It has been observed that mutations in these genes can have opposing effects on sensitivities to different partner drugs, which serve as the principle for designing triple ACTs and drug rotation. Although clinical ACT resistance is restricted to Southeast Asia, surveillance for drug resistance using in vivo clinical efficacy, in vitro assays, and molecular approaches is required to prevent or slow down the spread of resistant parasites.
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影响因子：
3.2
作者：
Adams T;Ennuson NAA;Quashie NB;Futagbi G;Matrevi S;Hagan OCK;Abuaku B;Koram KA;Duah NO
通讯作者：
Duah NO
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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
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DOI：
10.1016/s1473-3099(15)00487-9
发表时间：
2016-03
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.9
作者：
Bhisutthibhan, J;Meshnick, SR
通讯作者：
Meshnick, SR
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：
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