Mechanisms of macrolide synergy in Mycobacterium tuberculosis

大环内酯类药物在结核分枝杆菌中的协同作用机制

• 批准号: 10386174
• 负责人: Francesca Guglielmini Tomasi
• 金额: $ 2.16万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2022-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386174
• 关键词: Acetylation; Address; Amino Acyl Transfer RNA; Aminoacyl-tRNA hydrolase; Animal Model; Antibiotics; Bacterial Infections; Binding; Biological Assay; CRISPR interference; Cell Survival; Cells; Charge; Collaborations; Combined Modality Therapy; Communicable Diseases; Coupled; Creativeness; Critical Thinking; Data Analyses; Drops; Drug Metabolic Detoxication; Drug Targeting; Drug resistance in tuberculosis; Enzymes; Exposure to; Fellowship; Genes; Genetic; Goals; Grant; Growth; Human; Ligase; Liquid Chromatography; Macrolides; Mass Spectrum Analysis; Measures; Methods; Morbidity - disease rate; Mycobacterium smegmatis; Mycobacterium tuberculosis; Natural Resistance; Organism; Paper; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Play; Prevalence; Principal Investigator; Problem Solving; Protein Biosynthesis; Proteins; Public Health; Public Health Schools; Quality Control; RNA, Transfer, Amino Acid-Specific; Recording of previous events; Recycling; Research; Resistance; Ribosomes; Role; Sampling; System; Technical Expertise; Techniques; Testing; Toxin; Training; Transfer RNA; Transfer RNA Aminoacylation; Translations; Tuberculosis; Writing; acquired drug resistance; antibiotic tolerance; antitoxin; drug discovery; experimental study; fight against; fitness; genetic approach; global health; graduate student; improved; inhibitor; interest; knock-down; mortality; novel strategies; novel therapeutics; overexpression; pathogen; peptidyl-tRNA; premature; response; skills; synergism; tool; tuberculosis drugs; tuberculosis treatment

ABSTRACT I have been fortunate to combine my passions for scientific research and public health in my doctoral studies at the Harvard T. H. Chan School of Public Health. My goal is to combine creativity and technical skills in drug discovery efforts against infectious diseases of high morbidity and mortality. Dr. Eric Rubin's lab is the archetype for rigorous scientific training and creative problem-solving. He and I have established my core training goals. I hope not only to complete my proposed research plan, but also to continue sharpening skills in grant and paper writing, collaboration, critical thinking, and quantitative data analysis. An F31 Fellowship will propel me in my journey to become a principal investigator in the field of antibiotic research and discovery. Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), has been a leading cause of infectious disease morbidity and mortality for thousands of years. One major reason for its global persistence is the fact that Mtb is intrinsically resistant to most antibiotics. Current treatment requires months of combination therapy with drugs almost exclusively reserved for TB and that are not well-tolerated by patients. The high morbidity, mortality, and the growing prevalence of acquired drug resistance in TB motivate an urgent search for new drugs. If bacterial targets could be identified that synergize with existing drugs, such as to bring efficacy to antibiotics not currently effective against TB, they could advance our goal of treatment improvement. I have used a genetic approach to identify an essential Mtb enzyme that, when depleted, sensitizes this pathogen to existing antibiotics. Here, I propose to characterize the mechanisms of synergy between this Mtb gene and macrolide antibiotics, which bind the 50S ribosomal subunit to inhibit translation. Macrolides are inexpensive and well- tolerated antibiotics used to treat other infectious diseases. My gene of interest, pth, encodes the essential enzyme peptidyl tRNA hydrolase, a translation rescue factor that cleaves tRNA from peptides when they are prematurely released from stalled ribosomes. My approach to studying Pth as an antibiotic target draws on existing analytical techniques, as well as a new method using tRNA-sequencing that I have developed for studying charged tRNA pools. Investigating synergistic drug targets and their mechanisms of interaction will allow us to lend new efficacy to old compounds in the fight against TB. Additionally, new tools to study tRNA will allow us to expand our understanding of translation machinery in other organisms.

抽象的 我很幸运能够将我对科学研究和公共卫生的热情结合到我的博士学位中 在哈佛大学陈曾熙公共卫生学院学习。我的目标是将创造力和技术技能结合起来 针对高发病率和死亡率的传染病的药物发现工作。 Eric Rubin 博士的实验室是 严格的科学训练和创造性解决问题的原型。他和我建立了我的核心训练 目标。我不仅希望完成我提出的研究计划，还希望继续提高资助技能 以及论文写作、协作、批判性思维和定量数据分析。 F31 奖学金将推动 我正在成为抗生素研究和发现领域的首席研究员。 结核分枝杆菌 (Mtb) 是导致结核病 (TB) 的主要原因 几千年来传染病的发病率和死亡率。其在全球持续存在的一个主要原因是 事实上，结核分枝杆菌本质上对大多数抗生素具有耐药性。目前的治疗需要数月的联合治疗 使用几乎专门用于结核病且患者耐受性不佳的药物进行治疗。高 结核病的发病率、死亡率和获得性耐药性的日益流行促使人们迫切寻找 新药。如果能够识别出与现有药物具有协同作用的细菌靶标，例如为药物带来功效 目前抗生素对结核病无效，但它们可以推进我们改善治疗的目标。我用过 一种遗传方法来识别一种必需的结核分枝杆菌酶，当这种酶耗尽时，会使该病原体对现有的 抗生素。在这里，我建议描述该 Mtb 基因和大环内酯之间的协同机制 抗生素，结合 50S 核糖体亚基以抑制翻译。大环内酯类药物价格低廉且效果良好 用于治疗其他传染病的耐受抗生素。我感兴趣的基因 pth 编码必需的 肽基 tRNA 水解酶，一种翻译救援因子，可将 tRNA 从肽上切割下来 过早地从停滞的核糖体中释放出来。我研究 Pth 作为抗生素靶点的方法借鉴了 现有的分析技术，以及我开发的使用 tRNA 测序的新方法 研究带电 tRNA 池。研究协同药物靶点及其相互作用机制将 让我们能够为旧化合物提供新的功效来对抗结核病。此外，研究 tRNA 的新工具将 使我们能够扩大对其他生物体翻译机制的理解。