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.

摘要