Chemical Probes of Mycobacteria

分枝杆菌化学探针

• 批准号: 10595665
• 负责人: Laura L Kiessling
• 金额: $ 57.93万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595665
• 关键词: Antibiotic Therapy; Antibiotics; Antimycobacterial Agents; Architecture; Biogenesis; COVID-19; Cell Wall; Cell division; Cells; Cellular Morphology; Chemicals; Complex; Data; Detection; Disease; Drug resistance; Environment; Generations; Genus Mycobacterium; Goals; Grant; Granuloma; Human; Image; Immune; Immune Evasion; Immune system; Infectious Agent; Investigation; Knowledge; Label; Link; Lipids; Location; Lung; Macrophage; Mannose; Microbe; Monitor; Mycobacterium tuberculosis; Mycolic Acid; Necrosis; Osmosis; Pathogenicity; Persons; Phenotype; Polysaccharides; Predisposition; Process; Reaction; Reporter; Research; Resistance; Role; Stress; Time; Trehalose; Tuberculosis; Virulence; Visualization; analog; arabinofuranose; arabinogalactan; cell envelope; cell growth; fluorophore; functional group; immunoregulation; insight; lipoarabinomannan; mycobacterial; novel strategies; novel therapeutics; programs; resistant strain; response; stem; sugar; thiosugar; tool; uptake

Project Summary/Abstract Section The rise of resistant strains of Mycobacterium tuberculosis (Mtb) demands new approaches to combating this infectious agent. The survival of Mtb depends on the cell envelope, which is both durable and dynamic. Mycobacteria modulate their cell envelope composition to subsist in the harsh environments they encounter in the host. The proposed aims focus on developing new tools to probe, perturb, and observe changes in the mycobacterial cell envelope. The focus of Aim 1 is on visualizing arabinofuranose and mannose residues within the cell wall and the immunomodulatory lipoarabinomannan (LAM). In Aim 2, we shall develop a complementary probe that identifies methylthioxylofuranose (MTX)-capped LAM, a glycan that has been detected in pathogenic mycobacteria. The probes generated in Aims 1 and 2 can reveal how cell envelope composition varies under different conditions and between strains. In Aim 3, we shall deploy a fluorogenic probe to visualize the changing mycobacterial cell envelope in real time. This probe provides a means to explore phenotypic changes in the mycobacterial cell envelope upon antibiotic treatment or uptake into macrophages. By pursuing the three aims, we expect to uncover vulnerabilities in mycobacterial defenses that will lead to new antibiotic strategies. Significance: The overall objective of this application is to develop new chemical probes to understand how the mycobacteria modify and maintain their cell envelope to survive under the extreme and varied conditions they encounter in human hosts. We anticipate that this knowledge will ultimately lead to the identification of new strategies to treat tuberculosis (TB).

项目概要/摘要部分 结核分枝杆菌（Mtb）耐药菌株的增加需要新的方法来解决 对抗这种传染性病原体。结核分枝杆菌的生存依赖于细胞包膜，这是两者兼而有之。 持久和动态。分枝杆菌调节它们的细胞被膜组成以在细胞膜中生存。 它们在宿主体内遇到的恶劣环境。新的目标集中在开发新的 探测、扰动和观察分支杆菌细胞包膜变化的工具。的焦点 目的1是观察细胞壁内的阿拉伯呋喃糖和甘露糖残基， 免疫调节脂阿拉伯甘露聚糖（LAM）。在目标2中，我们将制定一项补充 一种识别甲硫基呋喃糖（MTX）封端的LAM的探针， 在致病分枝杆菌中检测到。目的1和2中产生的探针可以揭示细胞如何 包膜组成在不同条件下和菌株之间变化。在目标3中， 部署荧光探针以真实的实时观察变化的分枝杆菌细胞包膜。 这种探针提供了一种探索分枝杆菌细胞包膜表型变化的手段 在抗生素治疗或被巨噬细胞摄取后。通过实现这三个目标，我们希望 发现分枝杆菌防御系统的弱点，这将导致新的抗生素策略。 重要性： 本申请的总体目标是开发新的化学探针，以了解 分枝杆菌修改并维持它们的细胞包膜，以在极端环境下存活， 它们在人类宿主身上遇到的各种情况。我们预计，这些知识将 最终导致确定治疗结核病的新策略。