Chemogenomic Interrogation of Non-Genetic Drug Resistance in Plasmodium falciparum

恶性疟原虫非遗传耐药性的化学基因组学研究

• 批准号: 9261789
• 负责人: Olufunbi Damilola Fagbami
• 金额: $ 3.76万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261789
• 关键词: Africa South of the Sahara; Age; Amino Acids; Amino Acyl-tRNA Synthetases; Anabolism; Antimalarials; Binding; Biochemical; Biological; Biology; Cessation of life; Chemicals; Chemistry; Child; Chinese Traditional Medicine; Clinical; Contracts; Development; Disease; Dose; Drug Tolerance; Drug resistance; Drug usage; Enzymes; Eukaryota; Evolution; Genes; Genetic; Goals; Growth; Halofuginone; Hemoglobin; Homeostasis; Ice; Infection; Intervention; Isotopes; Knock-out; Label; Lead; Malaria; Mammalian Cell; Metabolic; Molecular; Morbidity - disease rate; Mutation; Natural Products; Parasites; Parasitic Diseases; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphotransferases; Plasmodium falciparum; Proline; Public Health; Resistance; Resolution; Risk; Role; Savings; Source; Stable Isotope Labeling; Starvation; Stress; Transfer RNA; Transfer RNA Aminoacylation; Up-Regulation; antipyretic; base; biological adaptation to stress; chemical genetics; clinically relevant; experimental study; febrifugine; genetic approach; high risk; improved; inhibitor/antagonist; insight; killings; metabolic profile; mortality; next generation; non-genetic; novel; novel therapeutics; prevent; proline-tRNA; resistance mechanism; resistance mutation; response; screening; tool; treatment strategy; uptake; vector

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.

抽象的 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 每年都有人感染并导致 584,000 人死亡，其中大部分是撒哈拉以南非洲地区的幼儿。新兴 对大规模使用药物的耐药性现在是控制疟疾的最大障碍之一。作为 耐药性问题出现在化学和生物学的交汇处，因此也必须找到解决方案。我的目标是 使用化学工具探索寄生虫生物学，以开发抗疟疾问题的新解决方案 反抗。 使用综合化学基因组学方法，我们鉴定了细胞质脯氨酰 tRNA 恶性疟原虫（PfcPRS）中的合成酶是长期寻找的卤常酮的生化靶点。 此外，我们发现了一种前所未有的寄生虫耐药机制，通过调节 脯氨酸稳态。在这个提案中，我试图了解寄生虫感知能力的分子基础 并对卤常酮产生耐药性。我将研究一种非遗传性的耐药机制 通过调查卤常酮引起的细胞内脯氨酸增加的主要来源来研究卤常酮 治疗。我还将通过评估 aaRS 抑制寄生虫的潜在机制 氨基酸反应在感知和响应 aaRS 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标 干预、预防和克服对 PfcPRS 抑制剂的耐药性，并可能确定协同作用 联合治疗策略。该提案的成功执行将使我们能够深入研究生物学 寄生虫的目的是为了找到新的致命弱点来利用。这将使我们走上拯救下一个的道路 疟疾的发病率和死亡率。