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Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria.
Annual Review of Microbiology ( IF 8.5 ) Pub Date : 2020-09-09 , DOI: 10.1146/annurev-micro-020518-115546
Kathryn J Wicht 1 , Sachel Mok 1 , David A Fidock 1, 2
Affiliation  

Understanding and controlling the spread of antimalarial resistance, particularly to artemisinin and its partner drugs, is a top priority. Plasmodium falciparum parasites resistant to chloroquine, amodiaquine, or piperaquine harbor mutations in the P. falciparum chloroquine resistance transporter (PfCRT), a transporter resident on the digestive vacuole membrane that in its variant forms can transport these weak-base 4-aminoquinoline drugs out of this acidic organelle, thus preventing these drugs from binding heme and inhibiting its detoxification. The structure of PfCRT, solved by cryogenic electron microscopy, shows mutations surrounding an electronegative central drug-binding cavity where they presumably interact with drugs and natural substrates to control transport. P. falciparum susceptibility to heme-binding antimalarials is also modulated by overexpression or mutations in the digestive vacuole membrane–bound ABC transporter PfMDR1 (P. falciparum multidrug resistance 1 transporter). Artemisinin resistance is primarily mediated by mutations in P. falciparum Kelch13 protein (K13), a protein involved in multiple intracellular processes including endocytosis of hemoglobin, which is required for parasite growth and artemisinin activation. Combating drug-resistant malaria urgently requires the development of new antimalarial drugs with novel modes of action.

中文翻译:


恶性疟原虫疟疾耐药的分子机制。

了解和控制抗疟药耐药性的传播,尤其是青蒿素及其伙伴药物的耐药性,是当务之急。恶性疟原虫对氯喹、阿莫地喹或哌喹具有抗性的恶性疟原虫氯喹抗性转运蛋白 (PfCRT)存在突变,这是一种驻留在消化液泡膜上的转运蛋白,其变异形式可以将这些弱碱 4-氨基喹啉药物转运出体外这种酸性细胞器,从而阻止这些药物结合血红素并抑制其解毒。通过低温电子显微镜解析的 PfCRT 结构显示了围绕带负电的中央药物结合腔的突变,推测它们可能与药物和天然底物相互作用以控制运输。恶性疟原虫对血红素结合抗疟药的敏感性也受到消化液泡膜结合 ABC 转运蛋白 PfMDR1(恶性疟原虫多药耐药 1 转运蛋白)的过度表达或突变的调节。青蒿素抗性主要由恶性疟原虫Kelch13 蛋白 (K13)的突变介导,该蛋白参与多种细胞内过程,包括血红蛋白的内吞作用,这是寄生虫生长和青蒿素激活所必需的。对抗耐药性疟疾迫切需要开发具有新作用模式的新型抗疟药物。

更新日期:2020-09-10
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