Investigation of late-stage mycobacterial cell wall biosynthesis

结核病（TB）是由结核分枝杆菌（Mycobacterium tuberculosis）引起的细菌性传染病。结核病影响着世界上很大一部分人口，特别是在贫困的情况下，结核病仍然是世卫组织领导的疾病控制工作的重中之重。M.结核病是一种非常成功的病原体，部分原因是其独特的细胞壁为宿主防御提供了几乎无法穿透的屏障，并有助于抵抗许多常见的抗生素，如青霉素。结核病是用四种一线药物的混合物治疗的，然而，日益增加的多药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击中新的目标。M的生存。结核病的关键在于其独特细胞壁的完整性，并且有助于细胞壁生物合成的酶经常成为新的药物样抑制剂的靶点。在这方面，更好地了解细胞壁组装将支持寻求新的疗法，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，了解参与这一途径的基因和酶如何工作是我们开发治疗这种疾病的新药的基础。希望通过对M.对于结核病，我们将能够找到“盔甲上的缝隙”，并通过开发新的药物靶点来开发新的疗法。我们的提议将为控制分支杆菌组装细胞壁方式的遗传和生化过程提供新的线索。我们将沿着两条线索进行调查。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以指导细胞包膜的最终成熟进行详细研究。其次，我们将阐明关键蛋白质的分子结构和生化机制，这些蛋白质是运输大型中间细胞壁成分穿过细胞内膜的核心，以及它们如何在分枝杆菌细胞表面组装它们。提高我们在这一领域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，在生物体表面工作的酶和蛋白质可能被证明是更容易获得的化疗靶点。在本项目结束时，我们将提供有关细菌病原体的重要信息，这是人类的祸害，并为分枝杆菌细胞壁生物合成机制提供新的见解。这项工作将对抗结核抑制剂的发现和开发产生直接影响。

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.