Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites.
Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites.
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DOI：
10.1128/mbio.01193-18
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发表时间：
2018-11-13
期刊：
影响因子：
6.4
通讯作者：
Odom John AR
中科院分区：
文献类型：
--
作者：
Guggisberg AM;Frasse PM;Jezewski AJ;Kafai NM;Gandhi AY;Erlinger SJ;Odom John AR
寄生虫代谢的独特和必要的方面是开发新的抗疟疾药物的极佳靶点。迫切需要更好地了解寄生虫的代谢和耐药机制。抗生素磷霉素的靶标是从葡萄糖合成必需的异戊二烯类化合物，是抗疟疾开发的候选药物。我们的报告发现了一种新的耐药机制，并进一步描述了寄生虫中的代谢调节因子家族。使用一种新的正向遗传方法，我们还发现了糖酵解酶PFK9中抑制耐药性的突变。因此，我们确定了一种意想不到的适应代谢侮辱的遗传机制，影响了寄生虫的适合性和抗疟疾药物的耐受性。在疟疾寄生虫恶性疟原虫中，从糖酵解中间产物合成异戊二烯类化合物是生存所必需的。抗疟药磷霉素(FSM)可抑制类异戊二烯的合成。在恶性疟原虫中，我们鉴定了HAD2(恶性疟原虫3D7_1226300[PF3D7_1226300])中的一个功能缺失突变是产生FSM抗性所必需的。酶学特性表明，HAD2是一种磷酸酶，属于卤酸脱卤酶样水解酶(HAD)超家族成员。利用耐药寄生虫的生长缺陷，我们选择了用于抑制HAD2介导的FSM耐药性的寄生虫，并在编码糖酵解酶磷酸果糖激酶9(PFK9)的位置发现了亚形态抑制子突变。代谢图谱显示，FSM抗性是通过增加甲基赤藓糖醇磷酸(MEP)途径和糖酵解中间产物的稳态水平来实现的，并证实了受抑制菌株中PFK9功能的降低。我们确定HAD2是疟疾寄生虫代谢和药物敏感性的新调节因子，并发现PFK9是寄生虫遗传代谢可塑性的新位点。我们的报告揭示了一个进化保守的代谢调节家族的生物学功能，并揭示了一种先前未描述的策略，即疟疾寄生虫通过该策略来适应细胞代谢失调。
Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials. In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation.
影响因子：
3.7
作者：
Ghorbal M;Scheidig-Benatar C;Bouizem S;Thomas C;Paisley G;Faltermeier C;Liu M;Scherf A;Lopez-Rubio JJ;Gopaul DN
通讯作者：
Gopaul DN