Chemogenomic Interrogation of Non-Genetic Drug Resistance in Plasmodium falciparum

摘要 疟疾是一个具有全球重要性的公共卫生问题。这种毁灭性的疾病感染了1.98亿人 每年有584，000人死于疟疾，其中大部分是撒哈拉以南非洲的儿童。新兴 对大规模使用的药物的抗药性现在是控制疟疾的最大障碍之一。为 抗药性的问题出现在化学和生物学的交界处，解决办法也必须如此。我的目标是 使用化学工具来探测寄生虫生物学，以开发新的解决方案来解决抗疟疾问题， 阻力 使用一个综合的化学基因组学方法，我们已经确定了细胞质脯氨酰tRNA 恶性疟原虫（PfcPRS）合成酶作为常山酮长期寻求的生化靶标。 此外，我们发现了一个前所未有的机制，药物耐受性的寄生虫通过调节 脯氨酸稳态在这个建议中，我试图了解寄生虫感知能力的分子基础， 并对常山酮产生抗药性我将研究一种非遗传的抵抗机制， 通过研究细胞内脯氨酸增加的主要来源，以响应常山酮 治疗我还将通过评估寄生虫中阿尔斯抑制的潜在机制， 氨基酸应答在感知和应答阿尔斯抑制中的作用。 从拟议的实验中获得的见解可以揭示化疗的新靶点 干预、预防和克服对PfcPRS抑制剂的耐药性，并潜在地鉴定协同增效作用， 联合治疗策略。成功执行这项提案将使我们能够深入研究生物学 为了找到新的致命弱点加以利用这将使我们走上拯救下一个 疟疾的发病率和死亡率对一代人的健康造成了很大的影响。

ABSTRACT Malaria is a public health problem of global importance. This devastating disease infects 198 million infections people every year and kills 584,000, mostly young children in sub-Saharan Africa. Emerging resistance to drugs used on a large scale is now one of the greatest obstacles to the control of malaria. As the problem of drug resistance arises at the interface of chemistry and biology, so too must the solution. My goal is to use chemical tools to probe parasite biology in order to develop new solutions to the problem of antimalarial resistance. Using an integrated chemogenomic approach, we have identified the cytoplasmic prolyl tRNA synthetase in Plasmodium falciparum (PfcPRS) as the long-sought biochemical target of halofuginone. Furthermore, we uncovered an unprecedented mechanism of drug-tolerance in the parasite by modulation of proline homeostasis. In this proposal, I seek to understand the molecular basis of the parasite's ability to sense and evolve resistance to halofuginone. I will investigate a non-genetic mechanism of resistance to halofuginone by investigating the primary source of increased intracellular proline in response to halofuginone treatment. I will also explore the underlying mechanisms of aaRS inhibition in the parasite by evaluating the role of the amino acid response in sensing and responding to aaRS inhibition. Insights gained from the proposed experiments could reveal novel targets for chemotherapeutic intervention, prevent and overcome resistance to PfcPRS inhibitors, and potentially identify synergistic combination treatment strategies. Successful execution of this proposal will enable us to delve into the biology of the parasite in order to find a new Achilles' heel to exploit. This will put us on the path to saving the next generation of people from the morbidity and mortality of malaria.