Chemogenomic Profiling of Plasmodium falciparum Drug Responses and Resistance

 描述（由申请人提供）：疟疾是一个毁灭性的全球健康问题，如果对一线抗疟药物的耐药性继续蔓延，情况将变得更糟。失去对恶性疟原虫的有效药物治疗，特别是青蒿素（ART）联合疗法（ACT）的损失，将是一场全球公共卫生灾难。最近，一种调节蛋白Kelch“K13-propeller”蛋白的多态性与ART药物的疗效丧失有关，但耐药机制尚不清楚。了解抗逆转录病毒药物耐药性（ART-R）的机制对于设计抑制ART-R进一步传播的ACT以及确定用于监测和遏制计划的其他分子标记物非常重要。不幸的是，缺乏关于大多数恶性疟原虫基因的实验验证的功能信息仍然是更好地理解ART-R和开发新的抗疟疾疗法的战略障碍。更好地了解寄生虫生理引擎中的基本代谢途径和脆弱性对于定义现有药物的作用机制、如何对这些药物产生耐药性以及有效联合治疗的分子策略至关重要。我们建议使用化学基因组学系统方法来定义与ART-R相关的关键途径，了解ART和其他抗疟伙伴药物的作用机制，并预测具有最佳协同抗寄生虫活性的药物联合治疗，以最大限度地减少耐药性的出现。

 DESCRIPTION (provided by applicant): Malaria is a devastating global health problem that will become much worse if resistance to frontline antimalarial drugs continues to spread. The loss of effective drug treatment of Plasmodium falciparum, especially the loss of artemisinin (ART) combination therapy (ACT), would be a global public health catastrophe. Recently, polymorphism in a regulatory protein, the Kelch "K13-propeller" protein was implicated in the loss of efficacy of ART drugs, but the mechanism of resistance is not understood. Understanding the mechanism of ART drug resistance (ART-R) is important for devising ACTs that inhibit further spread of ART-R and for identifying other molecular markers for surveillance and containment programs. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle for better understanding ART-R and for development of new anti-malarial therapeutics. Better knowledge of essential metabolic pathways and vulnerabilities in the parasite's physiologic engine are critical for defining mechanisms of action of existing drugs, how resistance develops to these drugs as well molecular strategies for effective combination therapies. We propose to use a chemogenomic systems approach to define critical pathways linked to ART-R, understand mechanisms of action of ART and other antimalarial partner drugs, and predict drug combination therapies with optimal synergistic anti-parasite activity to minimize the emergence of resistance.