A broad analysis of resistance development in the malaria parasite.
A broad analysis of resistance development in the malaria parasite.
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对疟原虫耐药性发展的广泛分析。
DOI：
10.1038/ncomms11901
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发表时间：
2016-06-15
影响因子：
16.6
通讯作者：
Winzeler EA
中科院分区：
文献类型：
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作者：
Corey VC;Lukens AK;Istvan ES;Lee MCS;Franco V;Magistrado P;Coburn-Flynn O;Sakata-Kato T;Fuchs O;Gnädig NF;Goldgof G;Linares M;Gomez-Lorenzo MG;De Cózar C;Lafuente-Monasterio MJ;Prats S;Meister S;Tanaseichuk O;Wree M;Zhou Y;Willis PA;Gamo FJ;Goldberg DE;Fidock DA;Wirth DF;Winzeler EA
在疟疾流行的地方，微生物对化疗的抗药性已经造成无数人死亡。化疗可能会失败，要么是由于预先存在的耐药性或耐药寄生虫的演变。在这里，我们使用一组不同的抗疟化合物来研究获得耐药性和对常见耐药等位基因的交叉耐药程度。我们使用一组15个寄生虫品系评估交叉抗性，这些品系携带pfatp 4、细胞色素bc 1、pfcarl、pfdhod、pfcrt、pfmdr、pfdhfr、细胞质脯氨酰t-RNA合成酶或hsp 90中的抗性赋予等位基因。随后，我们评估是否可以在几轮药物选择后获得耐药寄生虫。在48种体外选择中，有23种产生了耐药寄生虫，耐药发生时间为15至300天。我们的数据表明，预先存在的耐药性可能不是新靶点抗疟候选药物的主要障碍，将我们的注意力集中在快速杀伤化合物上可能会导致临床耐药性的缓慢出现。 目前还不清楚新的抗疟化合物是否会因为寄生虫的抗药性而在实地迅速失去效力。在这里，Corey等人研究了耐药性的获得以及常见耐药机制降低对50种不同抗疟化合物敏感性的程度。
Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance. It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al. investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.