Chemical Probes of Mycobacteria

项目摘要/摘要部分 结核分枝杆菌(Mtb)耐药株的崛起需要新的方法来应对 对抗这种感染性病原体。结核分枝杆菌的存活取决于细胞的包膜，它既是 经久耐用，充满活力。分枝杆菌调整它们的细胞膜成分以在 他们在宿主中遇到的恶劣环境。提议的目标集中在开发新的 用于探测、干扰和观察分枝杆菌细胞膜变化的工具。的关注点 目标1是可视化细胞壁和细胞壁中的阿拉伯呋喃和甘露糖残留量 免疫调节性阿拉伯甘露聚糖(LAM)。在目标2中，我们将制定一个补充方案 识别甲硫氧基呋喃(MTX)封端的LAM的探针，一种已被 在致病分枝杆菌中检测到。AIMS 1和2中产生的探针可以揭示细胞如何 在不同的条件下和不同的菌株之间，包膜成分不同。在目标3中，我们将 部署一个荧光探针，实时观察分枝杆菌细胞膜的变化。 该探针提供了一种探索分枝杆菌细胞膜表型变化的方法。 在抗生素治疗或被巨噬细胞摄取时。通过追求这三个目标，我们希望 发现分枝杆菌防御中的漏洞，这将导致新的抗生素策略。 重要意义： 这个应用程序的总体目标是开发新的化学探针，以了解 分枝杆菌修改和维持它们的细胞膜，以便在极端和 它们在人类宿主体内遇到的各种条件。我们预计，这一知识将 最终导致确定治疗结核病(TB)的新战略。

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).