Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89
Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89
复制标题
恶性疟原虫抗疟药内过氧化物 N-89 的基因组和生物学特征
DOI：
10.1016/j.gene.2019.144016
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发表时间：
2019
期刊：
影响因子：
3.5
通讯作者：
Kim Hye-Sook
中科院分区：
文献类型：
--
作者：
Morita Masayuki;Hayashi Kosuke;Sato Akira;Hiramoto Akiko;Kaneko Osamu;Isogawa Rena;Kurosaki Yuji;Miyoshi Shin-ichi;Chang Kyung-Soo;Wataya Yusuke;Kim Hye-Sook
疟疾寄生虫的耐药性仍然是影响抗疟治疗和疾病控制的一个问题。我们以前合成了一种抗疟内过氧化物，N-89，在体外和体内都有很高的抗疟效果。在本研究中，我们试图了解对N-89的耐药机制，通过建立一个高度耐N-89的克隆，命名为NRC 10 H，恶性疟原虫FCR-3株。我们使用全基因组测序和随后使用定量实时PCR通过表达谱分析来描述亲本FCR-3菌株和NRC 10 H克隆中的基因突变。NRC 10 H克隆中与耐药性、蛋白水解、糖磷脂酰肌醇锚生物合成和磷脂酰乙醇胺生物合成相关的7个基因表现出单个氨基酸取代。在这7个基因中，多药耐药蛋白2（mdr 2）变异体A532 S仅在NRC 10 H中发现。研究了该菌的遗传状况。NRC 10 H克隆和亲本FCR-3株之间的恶性疟原虫内质网驻留钙结合蛋白（PfERC）（N-89的潜在靶点）相似。这些发现表明，NRC 10 H中鉴定的7个基因的遗传改变，特别是armdr 2，可能引起抗疟内过氧化物N-89的耐药性。
Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effectsin vitroandin vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of theP. falciparumendoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particularmdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.