Metabolic Impact of Tryptophan Synthase Inhibition in Mycobacterium tuberculosis and Implications for Rational Combination Therapy

色氨酸合酶抑制对结核分枝杆菌的代谢影响以及合理联合治疗的意义

基本信息

批准号：
10066828
负责人：
Kyle Planck
金额：
$ 4.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066828
关键词：
Academic Medical Centers Anabolism Animal Model Antibiotic Therapy Antibiotics Antimycobacterial Agents Antitubercular Agents Biochemical Biochemical Pathway Biochemical Process Biochemistry Biology CRISPR interference Cause of Death Cells Chemicals Colony-forming units Combined Modality Therapy Communicable Diseases Complex Data Development Diet Dominant-Negative Mutation Drug Combinations Drug Controls Drug Targeting Drug resistance Enzymes Extreme drug resistant tuberculosis Feedback Fellowship Folic Acid Foundations Genes Genetic Goals Growth Human Infection Investigation Iron Knock-out Knowledge Laboratory Research Light Link Literature Medicine Mentorship Metabolic Metabolic Pathway Microbiological Techniques Microbiology Modality Molecular Target Mycobacterium tuberculosis New York City Nutrient Organism Pathogenesis Pathogenicity Pathway interactions Pharmacology Physiology Population Process Production Regulation Research Resistance Siderophores Signal Transduction Source Starvation Stress Structure Supplementation Surveys System Technical Expertise Techniques Technology Testing Toxic effect Tryptophan Tryptophan Synthase Tuberculosis Vitamin K 2 Vocational Guidance Western Blotting Work base career chemotherapy clinically relevant cost doctoral student drug action drug candidate drug development effective therapy experience fitness gene product inhibitor/antagonist interest knock-down liquid chromatography mass spectrometry member metabolomics microorganism mycobacterial novel novel strategies pathogen programs protein expression resistant strain response scaffold transcriptome sequencing transcriptomics treatment strategy tuberculosis drugs tuberculosis treatment

项目摘要

PROJECT SUMMARY Kyle Planck is a PhD Student in the pharmacology program at Weill Cornell Medicine in New York City, where he is a member of the Rhee research laboratory. His research interests include developing a deeper understanding of the biochemical processes at work in pathogenic microorganisms and employing this knowledge to formulate clinically relevant treatments for the infections they cause. At Weill Cornell, Kyle carries out this work specifically within the context of tuberculosis (TB), which is the world’s leading cause of death from an infectious disease. This fellowship application details a research plan that incorporates the acquisition of technical skills with mentorship and career guidance in order to prepare him for his career goal of establishing an independent research laboratory at an academic medical center. Kyle has extensive research experience in biology, biochemistry, and pharmacology, and he brings that research foundation to his graduate work and this proposal, which integrates systems level “omics” analytical approaches with classical microbiological and biochemical techniques. The goal of this project is to characterize the metabolic effects of inhibiting the tryptophan biosynthesis pathway, which is essential to the survival of Mycobacterium tuberculosis (Mtb)—the causative agent of TB—and is being pursued as a source of potential drug targets. The project has two aims: to determine the mechanism of killing elicited by allosteric chemical inhibitors of tryptophan synthase (TrpAB), which our preliminary data suggests to be more complex than simple enzyme product depletion, and to survey whether TrpAB inhibition results in collateral vulnerabilities in other metabolic pathways that may be targetable as well. By carrying out these investigations, Kyle hopes to provide evidence for the mechanism of action of these drug candidates, shed light on the process of tryptophan biosynthesis and its regulation in Mtb, and reveal novel possibilities for combination therapy, which is required for the effective treatment of tuberculosis. This research strategy proposes to answer these questions by incorporating standard microbiological techniques such as growth curves and colony-forming unit enumeration in tandem with cutting-edge technologies such as inducible genetic knockdown strains, RNA sequencing, targeted and untargeted LC/MS-based metabolomics, and CRISPR interference to probe the biology of Mtb in the context of TrpAB inhibition compared to no drug controls. Systems level omics modalities such as metabolomics and transcriptomics will be used to survey the genetic and metabolic networks controlling tryptophan biosynthesis in Mtb, which will then be validated with genetic and biochemical approaches.

项目摘要凯尔·普朗克（Kyle Planck 他是Rhee研究实验室的成员。了解致病微生物工作中的生化过程并采用这一点凯尔（Kyle）的知识为其引起的感染而临床相关。在结核病（TB）的背景下专门删除这项工作感染性疾病。具有指导和职业指导的技术技能，以便为他的职业做好准备学术医学中心的独立研究实验室。凯尔（Kyle）在生物学，生物化学和药理学方面拥有丰富的研究经验，他带来了该研究他的研究生工作和该建议的基础，该提议整合了系统级别的“ OMIC”分析方法使用经典的微生物和生化技术。抑制色氨酸生物合成途径的影响，这对于分枝杆菌的存活至关重要结核病（MTB） - TB t的病因被作为潜在药物靶标的项目有两个目的：确定色氨酸变构化学抑制剂引起的杀死机制 Synthhase（TRPAB），我们的初步数据比简单酶产物更复杂部署，并调查TRPAB抑制是否会导致其他代谢途径中的附带脆弱性这也可能是针对性的。这些候选药物的机制，阐明了色氨酸生物合成及其的过程 MTB中的调节和组合疗法的启示，这是有效的结核病的治疗。该研究策略通过合并标准微生物技术来提出这些问题的答案例如增长曲线和形成菌落形成单位单位单位枚举与尖端技术（例如可诱导的遗传敲低菌株，RNA测序，基于LC/MS的靶向和未靶向的代谢组学，与无药物相比控制系统级别。在MTB中控制色氨酸生物合成的遗传和代谢网络，并将其验证。遗传和生化方法。