The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly and the identification of potential new drug targets

结核分枝杆菌是结核病（TB）的病因，是世界上死亡率和发病率的主要细菌负担。世界上三分之一的人口感染了结核病，它与艾滋病毒一起是一个迫切需要解决的严重问题。结核病是一种贫困疾病，主要影响处于生产年龄的年轻人，主要发生在发展中国家。世界卫生组织的最新报告指出，2011年报告了880万新发结核病病例，140万人死于结核病，相当于每天约有4000人死亡。在英国，报告了7000例新的结核病病例，大多数在大城市，75%的病例不是在英国出生的。可以说，在全球范围内，结核分枝杆菌是影响人类的最重要的单一传染病。细菌被包裹在细胞壁中，保护生物体不受直接环境的影响。此外，幸运的是，它们也代表了青霉素等可用于治疗细菌感染药物的重要靶点。然而，结核分枝杆菌具有独特的细胞壁，其组成与其他细菌不同；特别是它含有大量独特的脂质（脂肪）、糖和网状结构。虽然有一些药物可以特异性地影响结核分枝杆菌细胞壁，但目前的结核病治疗持续6个月，并且对经常提前停止治疗的患者具有潜在毒性。此外，治疗效果受到多药耐药和广泛耐药（MDR和XDR）结核分枝杆菌菌株的出现的威胁。拟议的研究将增加我们对围绕结核分枝杆菌“细胞包膜”的基本生物学的认识，并有可能产生数据，这些数据将导致发现新的药物靶点，并有可能描述具有确定作用模式的新的“命中导向”化学实体的特征。首先，我们将建立在我们之前对细胞包膜的主要“脂肪”的合成的研究，称为霉菌酸和特定抑制剂的作用模式。其次，我们将扩展我们对“糖”组装所涉及的酶的特征，这些“糖”组成了结核分枝杆菌中发现的关键多糖，其中包括大分子阿拉伯半乳聚糖、脂阿拉伯甘露聚糖和α -葡聚糖。第三，我们将把我们对肽聚糖合成（覆盖细胞的潜在分子“网”）的研究整合到我们以结核分枝杆菌“细胞包膜”为中心的研究框架中。本应用程序的研究将增加我们对结核杆菌基本生物学的认识，并有可能对人类健康产生影响，在国内和国际上都有广泛的益处。特别是，我们提出的研究将有潜力确定新的药物靶点，并有助于开发新的抗结核化合物。

Mycobacterium tuberculosis is the cause of tuberculosis (TB) and is the leading bacterial burden of mortality and morbidity in the world. One third of the world's population is infected with TB, and in conjunction with HIV represents a serious problem that urgently needs addressing. TB is a disease of poverty and mostly affects young adults in their productive years, mostly in the developing world. The most recent report from the World Health Organisation states that in 2011, 8.8 million new cases of TB were reported and that 1.4 million people died from TB, corresponding to approximately 4000 deaths daily. In the UK, there were 7000 new cases of TB reported, mostly in large cities, and 75% of cases were in individuals not born in the UK. It can be argued that, globally, M. tuberculosis is the single most important infectious agent affecting mankind. Bacteria are enclosed in a cell wall which protects the organism from its immediate environment. Moreover, fortuitously, they also represent important targets for drugs like penicillin that can be used to treat bacterial infections. However, M. tuberculosis has a distinctive cell wall that differs in composition from that of other bacteria; in particular it contains an exceptional amount of unique lipids (fats), sugars, and a mesh-like structure. Although, there are drugs that specifically affect the M. tuberculosis cell wall, the current treatment for TB lasts 6 months and is potentially toxic to patients who often cease treatment early. Moreover, the efficacy of treatment is threatened by the emergence of multi-drug and extensively-drug resistant (MDR and XDR) strains of M. tuberculosis. The proposed research will increase our knowledge as to the basic biology surrounding the M. tuberculosis 'cell envelope' and has the potential to generate data that will lead to the discovery of novel drug targets and potentially the characterisation of new 'hit-to-lead' chemical entities with a defined mode of action. Firstly, we will build on our previous studies on the synthesis of the major 'fats' of the cell envelope, termed mycolic acids and the mode of action of specific inhibitors. Secondly, we will extend our characterisation of the enzymes involved in the assembly of the 'sugars' which make up the key polysaccharides found in M. tuberculosis, which includes the macromolecules arabinogalactan, lipoarabinomannan and alpha-glucan. Thirdly, we will integrate our studies on peptidoglycan synthesis, the underlying molecular 'mesh' that covers the cell, into our framework of studies centered on the M. tuberculosis 'cell envelope'. The research in this application will increase our knowledge into the basic biology of the tubercle bacillus and has the potential to impact upon human health, with wide-reaching benefits both nationally and internationally. In particular, our proposed studies will have the potential to identify novel drug targets and aid in the development of new anti-tubercular compounds.