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).

项目摘要/摘要部分 结核分枝杆菌（MTB）抗性菌株的兴起需要新的方法 打击这种传染性药物。 MTB的存活取决于细胞包膜，这两者都是 耐用和动态。分枝杆菌调节其细胞信封成分以固定在 他们在主机中遇到的恶劣环境。拟议的旨在关注开发新的 探测，扰动和观察分枝杆菌细胞包膜变化的工具。重点 AIM 1是在细胞壁和细胞壁内可视化阿拉伯呋喃糖和甘露糖残基 免疫调节性脂肪脂动蛋白曼南（LAM）。在AIM 2中，我们将发展一个补充 识别甲基噻思外呋喃糖（MTX）覆盖的LAM的探针，一种已成为的聚糖 在致病性分枝杆菌中检测到。目标1和2中生成的探针可以揭示细胞的方式 包络组成在不同条件下和菌株之间有所不同。在AIM 3中，我们将 部署荧光探针以实时可视化不断变化的分枝杆菌细胞包膜。 该探针提供了一种探索分枝杆菌细胞信封中表型变化的手段 抗生素治疗或吸收巨噬细胞。通过追求这三个目标，我们希望 发现会导致新的抗生素策略的分枝杆菌防御中的脆弱性。 意义： 该应用的总体目的是开发新的化学探针，以了解 分枝杆菌修改并保持其细胞信封以在极端和 他们在人类宿主中遇到的各种条件。我们预计这些知识将会 最终导致鉴定了治疗结核病（TB）的新策略。