Targeting trans-translation to kill M. tuberculosis non-replicating persister cells

靶向反式翻译杀死结核分枝杆菌非复制持久细胞

• 批准号: 10514636
• 负责人: ANTHONY D BAUGHN
• 金额: $ 66.03万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514636
• 关键词: Acute; Animals; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Bacillus; Bacteria; Binding; Biochemical; Biology; Cells; Cessation of life; Chemical Structure; Chemicals; Chronic; Development; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Drug usage; Drug-resistant Neisseria Gonorrhoeae; Escherichia coli; Eukaryota; Experimental Genetics; Future; Genetic; Goals; Growth; Impairment; In Vitro; Individual; Infection; Knowledge; Lead; Libraries; Macrophage; Metabolic Clearance Rate; Modeling; Molecular; Molecular Probes; Molecular Target; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis complex; Oral; Organism; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Physiology; Population; Predisposition; Property; Research; Resistance; Ribosomes; Role; Sterilization; Stress; Structure; Testing; Tissues; Translations; Tuberculosis; Validation; Work; World Health; acute infection; chronic infection; design; drug candidate; drug development; efficacy evaluation; efficacy testing; experimental study; genetic approach; in vivo; inhibitor; lead optimization; mouse model; mutant; novel; resistant strain; side effect; small molecule inhibitor; structural biology; therapeutic development; tool; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ABSTRACT The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis. One of the critical impediments to developing drugs that are effective against these deadly MTB strains is the lack of new antibiotic targets. The trans-translation pathway for resolving stalled ribosomes is a potential target for drug development because it is required for growth of MTB in culture. The recent identification of small molecule inhibitors of trans-translation provides essential tools to determine if trans-translation can be an antibiotic target. The long-term goal of this project is to understand the role of trans-translation in MTB and to exploit this pathway for antibiotic development. The overall objective of this proposal is to evaluate the role of trans-translation during MTB infection in vivo. The central hypothesis of this work is that inhibition of trans-translation during MTB infection will lead to death of all populations of bacteria, including actively replicating cells and non-replicating persister bacilli. The rationale that underlies the proposed research is that validation of trans-translation as an anti-TB target will lead to rapid development of new antibiotics that will dramatically shorten TB treatment times and lead to sterilization of infected tissues. The proposed research will also make significant contributions to the fundamental scientific understanding of MTB physiology by determining the role of trans-translation in this organism. The specific aims of this proposal are to identify the molecular targets of trans-translation inhibitors in MTB, to evaluate the essential role of trans- translation in survival of MTB under host-relevant conditions, and to characterize the anti-tubercular activity of acylaminooxadiazole compounds. The proposed experiments use genetic tools and small molecule inhibitors of trans-translation to determine if trans-translation is required under conditions that approximate normal MTB physiology, such as growth in macrophages and during infection in mice. The results of these experiments will provide the basis for understanding the role of trans-translation during stress and infection in bacteria as well as determining if this pathway can be targeted for drug development. Biochemical and genetic approaches will be used to identify the molecular targets of active compounds, and structural studies will reveal the molecular basis of activity. Results from these studies will allow future high-level optimization of drug candidates. By targeting a pathway that has not been used for antibiotic development, this project will yield new compounds that can be used individually or in combination with existing tuberculosis therapies.

项目概要/摘要 对大多数或所有可用抗生素具有耐药性的结核分枝杆菌 (MTB) 菌株的出现 给结核病的治疗带来了严重的问题。开发药物的主要障碍之一 能够有效对抗这些致命的 MTB 菌株的原因是缺乏新的抗生素靶点。反式翻译途径 解决停滞核糖体的问题是药物开发的潜在目标，因为它是核糖体生长所必需的 山地车文化。最近发现的反式翻译小分子抑制剂提供了重要的工具 以确定反式翻译是否可以成为抗生素靶点。该项目的长期目标是了解 反式翻译在 MTB 中的作用并利用该途径进行抗生素开发。总体目标 该提案的目的是评估反式翻译在体内 MTB 感染过程中的作用。中心假设为 这项工作是在 MTB 感染期间抑制反式翻译将导致所有细菌群体的死亡， 包括活跃复制的细胞和非复制的持久性杆菌。拟议的基本原理 研究表明，反式翻译作为抗结核靶标的验证将导致新药的快速开发 抗生素将大大缩短结核病治疗时间并导致受感染组织的灭菌。这 拟议的研究还将对 MTB 的基本科学理解做出重大贡献 通过确定反式翻译在该生物体中的作用来进行生理学研究。该提案的具体目标是 确定 MTB 中反式翻译抑制剂的分子靶点，评估反式翻译的重要作用 在宿主相关条件下翻译 MTB 的存活，并表征 MTB 的抗结核活性 酰氨基恶二唑化合物。拟议的实验使用遗传工具和小分子抑制剂 trans-translation 以确定在接近正常 MTB 的条件下是否需要进行 trans-translation 生理学，例如巨噬细胞的生长和小鼠感染期间的生长。这些实验的结果将 为理解细菌应激和感染期间反式翻译的作用提供基础 确定该途径是否可以作为药物开发的目标。生物化学和遗传学方法将 用于识别活性化合物的分子靶标，结构研究将揭示分子基础 的活动。这些研究的结果将使未来候选药物的高水平优化成为可能。通过瞄准一个 尚未用于抗生素开发的途径，该项目将产生可用于抗生素开发的新化合物 单独使用或与现有的结核病疗法联合使用。