How does tuberculosis eat its own cell wall?

分枝杆菌拥有细菌王国中设计最复杂的细胞壁之一。构成细胞壁的成分都对分枝杆菌在农业和人类中的毒力有重大影响，即分别对牛（如牛分枝杆菌）和人类（结核分枝杆菌）等重要动物的毒力有重大影响。分枝杆菌细胞壁的基础层由一种叫做肽聚糖的异聚物组成。这种聚糖-肽缀合物保护细胞免受膨胀压力，并为整个细胞壁提供支架。尽管它很重要，但我们对这堵墙是如何建造和拆除的了解并不完全。在其他生物体中，PBPs已被确定在肽聚糖合成/重塑中发挥过多的作用。结核分枝杆菌基因组编码十多种青霉素结合蛋白，其中大部分功能尚未被探索。PBPs的关键功能参与，如细胞分裂和延伸，已被证明对大肠杆菌等生物很重要。本研究将探讨结核分枝杆菌PBPs在结核分枝杆菌中的作用。为了了解结核分枝杆菌肽聚糖的生物合成、重塑和降解，我们将利用牛分枝杆菌BCG的有序单基因缺失文库以及海洋分枝杆菌、耻垢分枝杆菌、结核分枝杆菌和大肠杆菌菌株的靶向突变研究。我们将在多种条件下评估缺乏每种非必需PBPs的菌株的适应度，以便我们更好地了解单个PBPs对生物体的作用。这将使我们能够确定个体PBPs是否在压力下变得更重要，例如pH变化，氧化还原或抗菌化合物，这些都与结核分枝杆菌感染有关。形态学研究将确定任何PBPs的缺失是否会导致细胞分裂或形状的缺陷。这将与纯化PBPs的生化和结构分析相结合，使我们能够询问它们的催化功能。该项目将使我们更好地了解结核分枝杆菌在环境和感染动态背景下繁殖和生存的机制。

Mycobacteria possess one of the most intricately designed and complex cell walls within the bacterial kingdom. The components that make up the cell wall all significantly contribute to the virulence of mycobacteria both agriculturally and in humans i.e. in important animals such as cows (e.g. Mycobacterium bovis) and humans (Mycobacterium tuberculosis) respectively. The base-layer of the mycobacterial cell wall is comprised of a heteropolymer called peptidoglycan. This glycan-peptide conjugate protects the cell from its turgor pressure, and provides a scaffold for the entire cell wall. Despite its importance we have an incomplete knowledge of how this wall is constructed and dissembled. In other organisms PBPs have been identified to a plethora of roles in peptidoglycan synthesis/remodelling. The M. tuberculosis genome encodes more than ten penicillin binding proteins, most of which the functions have not been explored. Key functional involvement for PBPs such as cell division and elongation have been shown to be important for organisms such as E. coli. This study will investigate and identify the function of the mycobacterial PBPs in M. tuberculosis. To understand the biosynthesis, remodeling and degradation of M. tuberculosis peptidoglycan, we will take advantage of an ordered, single-gene deletion library in M. bovis BCG as well as targeted mutational studies in strains of Mycobacterium marinum, Mycobacterium smegmatis, M. tuberculosis and E. coli. We will evaluate the fitness of strains lacking each of the non-essential PBPs under a wide variety of conditions, so that we can better understand the role of individual PBPs to the organism. This will allow us to determine if individual PBPs become more important under stress such as pH variation, redox or antimicrobial compounds which are all relevant to M. tuberculosis infection. Morphological studies will determine if the loss of any PBPs result in defects in cell division or shape. This will be paired with biochemical and structural analysis of purified PBPs to allow us to interrogate their catalytic function. This project will give us a better understanding of the mechanisms M. tuberculosis utilises for reproduction and survival in the context of environmental and infection dynamics.