Discovering resistance-resistant antimalarial drug target

项目摘要/摘要 疟疾仍然是全球卫生的主要负担，感染了2.2亿多人，造成400多人死亡。 每年一千人。尽管过去15年来国际社会加强努力， 疟疾降低了全世界的疟疾发病率，但近年来这一进展停滞不前。 抗疟疾药物是减少疾病和传播的基础，但耐药性已经发展 1945年以来开发的每一种抗疟药物， 目前的一线青蒿素综合疗法。这种寄生虫容易发展 耐药性清楚地表明，迫切需要创新的抗疟药物发现方法， needed.在这里，我们提出了两种不同的策略，旨在发现抗疟药物的目标， 该抗性将难以在田间产生。第一种方法将描述代谢 疟疾寄生虫在对主要药物产生耐药性后获得的适应性，重点是 识别耐药寄生虫的新型代谢依赖性（脆弱性）。我们建议雇用 我们在疟原虫代谢组学特征方面的丰富经验 恶性疟原虫，比较药物敏感和耐药寄生虫的生化结构。 代谢组学将用于阐明耐药寄生虫中改变的代谢途径， 揭示了附带的敏感性，我们将验证作为假定的药物靶点，使用小分子 途径抑制剂或相关靶酶的遗传敲除。最终目标将是 这些附带的敏感性与主要药物一起将寄生虫锁定在药物敏感的 状态，因为初级电阻所需的适应不再可用，因此提供了一个 持久的互补性联合治疗对于第二种策略，我们建议发现主机 这些代谢过程对支持恶性疟原虫的血液阶段发育至关重要。血液 疟疾寄生虫生命周期的各个阶段都是疟疾学和人与人之间疾病传播的原因。 蚊子传播寄生虫，并严重依赖于人类血清中的营养物质。但我们 我发现不同的人血清批次在支持寄生虫生长的能力上是高度可变的 和传输。为了鉴定与寄生虫表型读数相关的血清代谢物，我们 建议利用我们的代谢组学方法结合标准寄生虫生长， 传递测定。使用来自健康供体的血清批次，这种方法将自然识别 寄生虫所依赖的、可变的并且因此潜在地可定向的主机进程。靶向 宿主因素使寄生虫失去了进化控制，降低了抗药性的可能性 出现。总之，该提案旨在解决抗疟药物耐药性这一持续存在的问题 通过评估两种发现耐药药物靶点的新策略来开发。

PROJECT SUMMARY/ABSTRACT Malaria continues to be a major burden on global health, infecting over 220 million and killing over 400 thousand people annually. Although the past fifteen years of enhanced international efforts to eradicate malaria has reduced malaria incidence worldwide, this progress has stagnated in recent years. Antimalarial drugs are foundational in reducing disease and transmission, but resistance has developed within twelve years of clinical introduction to every antimalarial drug developed since 1945 including the current front-line artemisinin-based combination therapies. This ease with which parasites develop resistance clearly indicates that innovative approaches to antimalarial drug discovery are urgently needed. Here we propose two separate strategies designed to discover antimalarial drug targets for which resistance will be difficult to develop in the field. The first approach will characterize metabolic adaptations acquired by malaria parasites upon becoming resistant to a primary drug, with a focus on identifying novel metabolic dependencies (vulnerabilities) of resistant parasites. We propose to employ our extensive experience in metabolomic characterization of the malaria parasite, Plasmodium falciparum, to compare drug-sensitive and drug-resistant parasite biochemical architectures. Metabolomics will be used to elucidate altered metabolic pathways in resistant parasites in order to reveal collateral sensitivities that we will validate as putative drug targets using either small molecule pathway inhibitors or genetic knockdowns of relevant target enzymes. The ultimate goal will be to target these collateral sensitivities together with the primary drug to lock the parasite into a drug-sensitive state, as the adaptations required for primary resistance are no longer available, thus providing an enduring, complementary combination therapy. For the second strategy, we propose to discover host metabolic processes that are critical to support blood-stage development of P. falciparum. The blood stages of the malaria parasite life cycle are responsible for both the symptomology and the human-to- mosquito transmission of the parasite, and critically rely on nutrients from human serum. However, we have found that different human serum lots are highly variable in their ability to support parasite growth and transmission. To identify serum metabolites that correlate with parasite phenotypic readouts, we propose to utilize our metabolomic approaches in combination with standard parasite growth and transmission assays. Using serum lots from healthy donors, this approach will identify naturally variable, and thus potentially targetable, host processes upon which the parasite is reliant. Targeting host factors takes the evolutionary control away from the parasite, reducing the probability of resistance emergence. In all, this proposal seeks to address the persistent problem of antimalarial drug resistance development by evaluating two new strategies for discovering resistance-resistant drug targets.