Investigation of late-stage mycobacterial cell wall biosynthesis

结核病(TB)是由结核分枝杆菌引起的一种细菌性传染病。在世卫组织领导的疾病控制努力中，结核病仍然是一个最优先事项，影响着世界大部分人口，特别是在贫困的情况下。结核分枝杆菌是一种非常成功的病原体，部分原因是它独特的细胞壁为宿主防御提供了几乎无法穿透的屏障，并导致了对许多常见抗生素的耐药性，如青霉素。结核病是用四种一线药物组成的鸡尾酒治疗的，然而，不断增加的多重耐药性损害了这种方案的疗效。人们普遍认为，扭转全球结核病流行需要新的抑制剂达到新的目标。结核分枝杆菌的生存关键在于其独特的细胞壁的完整性，而有助于细胞壁生物合成的酶往往成为新药类抑制剂的靶标。在这方面，对细胞壁组装的更好理解将支持对新疗法的探索，这是迫切需要的。分枝杆菌细胞壁是通过一系列复杂的生物合成“步骤”建立的，了解这一途径中涉及的基因和酶是如何工作的，这是我们开发治疗这种疾病的新药的基础。希望通过研究结核分枝杆菌复杂的细胞壁生物化学，我们将能够找到“盔甲上的下巴”，并通过开发新的药物靶点来开发新的治疗方法。我们的提议将为控制分枝杆菌组装细胞壁的遗传和生化过程提供新的线索。我们将沿着两条线进行调查。首先，我们计划对控制细胞壁形成后期阶段的遗传过程以及这些基因产物如何相互作用进行详细的研究，以指导细胞被膜的最终成熟。其次，我们将阐明关键蛋白质的分子结构和生化机制，这些蛋白质是通过细胞内膜运输大的中间细胞壁成分的核心，以及它们如何将它们组装在分枝杆菌细胞表面。提高我们在这方面的知识是至关重要的，因为发生在细菌细胞“表面”的生化过程比细胞内的反应更容易受到小分子的抑制。因此，工作在生物体表面的酶和蛋白质可能被证明是更容易进行化疗的目标。在本项目结束时，我们将提供关于一种危害人类的细菌病原体的重要信息，并为分枝杆菌细胞壁生物合成的机制提供新的线索。这项工作将对抗结核抑制剂的发现和发展产生直接影响。

Tuberculosis (TB) is a bacterial infectious disease caused by the organism Mycobacterium tuberculosis. Affecting large parts of the world's population, in particular in the context of poverty, TB remains a top priority among WHO-led disease containment efforts. M. tuberculosis is an extremely successful pathogen, in part because its unique cell wall provides an almost impenetrable barrier to host defences and contributes to resistance against many common antibiotics, such as penicillin. TB is treated with a cocktail of four frontline drugs, however increasing multi-drug resistance compromises the efficacy of this regimen. It is generally agreed that reversing the global TB epidemic requires new inhibitors hitting novel targets. Survival of M. tuberculosis rests critically on the integrity of its unique cell wall, and enzymes contributing to cell wall biosynthesis often emerge as the targets of new drug-like inhibitors. In this regard, a better understanding of cell wall assembly will support the quest for new therapies, which are urgently required. The mycobacterial cell wall is built through a series of complex biosynthetic "steps" and understanding how the genes and enzymes involved in this pathway work is fundamental for us to develop new drugs to treat this disease. It is hoped that by investigating the complex cell wall biochemistry of M. tuberculosis, we will be able to find a "chink in the armour" and develop new therapies by exploiting novel drug targets.Our proposal will shed new light on the genetic and biochemical processes that govern the way in which mycobacteria assembles its cell wall. We will follow two lines of investigation. Firstly, we plan to undertake a detailed investigation of the genetic processes that govern the latter stages of cell wall formation and how these gene products interact with each other in order to direct the final maturation of the cell envelope. Secondly, we will elucidate the molecular structures and biochemical mechanisms of the key proteins that are central to transporting large intermediate cell wall components across the inner membrane of the cell and how they assemble them on the mycobacterial cell surface. Improving our knowledge in this area is crucial because biochemical processes that occur on the "surface" of bacterial cells lend themselves more susceptible to inhibition by small molecules than reactions within the cell. Hence, enzymes and proteins that work at the surface of an organism may prove the more accessible targets to chemotherapy.At the end of this project, we will have provided important information about a bacterial pathogen which is a scourge to humanity and shed new light on the mechanisms of cell wall biosynthesis in mycobacteria. This work will have a direct impact on the discovery and development of anti-tubercular inhibitors.