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

结核分枝杆菌细胞包膜：解开复杂的细胞壁组装并识别潜在的新药物靶点

• 批准号: MR/K012118/1
• 负责人: Gurdyal Besra
• 金额: $ 185.45万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK012118%2F1
• 关键词: Mycobacterium; tuberculosis; Cell; Envelope; unravelling

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.

结核分枝杆菌是结核病(TB)的病因，是世界上最大的致死和致病细菌负担。世界上三分之一的人口感染了结核病，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，主要影响年富力强的年轻人，主要是在发展中国家。世界卫生组织的最新报告指出，2011年，报告了880万新的结核病病例，140万人死于结核病，相当于每天约4000人死亡。在英国，新报告的结核病病例有7000例，大部分发生在大城市，75%的病例发生在非英国出生的个人身上。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病原体。细菌被包裹在细胞壁中，以保护有机体免受其直接环境的影响。此外，幸运的是，它们也是青霉素等可用于治疗细菌感染的药物的重要靶点。然而，结核分枝杆菌有一个独特的细胞壁，在组成上与其他细菌不同；特别是它含有大量独特的脂类(脂肪)、糖和网状结构。尽管有专门影响结核分枝杆菌细胞壁的药物，但目前对结核病的治疗持续6个月，对经常提前停止治疗的患者具有潜在的毒性。此外，结核分枝杆菌多药耐药和广泛耐药(MDR和XDR)菌株的出现威胁着治疗效果。这项拟议的研究将增加我们对结核分枝杆菌“细胞膜”周围的基本生物学的了解，并有可能产生数据，从而发现新的药物靶标，并可能用确定的作用模式表征新的“命中到铅”的化学实体。首先，我们将建立在我们以前的研究基础上，细胞被膜的主要‘脂肪’的合成，称为真菌酸和特定的抑制物的作用方式。其次，我们将扩展我们对组成结核分枝杆菌关键多糖的‘糖’组装所涉及的酶的特征，其中包括大分子阿拉伯半乳聚糖、脂肪阿拉伯甘露聚糖和α-葡聚糖。第三，我们将把我们对肽聚糖合成的研究整合到我们以结核分枝杆菌“细胞外膜”为中心的研究框架中。这一应用领域的研究将增加我们对结核杆菌基础生物学的了解，并有可能对人类健康产生影响，对国内和国际都有广泛的好处。特别是，我们建议的研究将有可能确定新的药物靶点，并有助于开发新的抗结核化合物。

项目成果

Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen.

• DOI: 10.1038/srep38986
• 发表时间: 2016-12-16
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cox JA;Mugumbate G;Del Peral LV;Jankute M;Abrahams KA;Jervis P;Jackenkroll S;Perez A;Alemparte C;Esquivias J;Lelièvre J;Ramon F;Barros D;Ballell L;Besra GS
• 通讯作者: Besra GS

Mycobacterial cell wall biosynthesis: a multifaceted antibiotic target.

• DOI: 10.1017/s0031182016002377
• 发表时间: 2018-03
• 期刊: Parasitology
• 影响因子: 2.4
• 作者: Abrahams KA;Besra GS
• 通讯作者: Besra GS

Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.

通过靶向亚基界界面来抑制分枝杆菌色氨酸合酶。

• DOI: 10.1038/s41598-017-09642-y
• 发表时间: 2017-08-25
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Abrahams KA;Cox JAG;Fütterer K;Rullas J;Ortega-Muro F;Loman NJ;Moynihan PJ;Pérez-Herrán E;Jiménez E;Esquivias J;Barros D;Ballell L;Alemparte C;Besra GS
• 通讯作者: Besra GS

Identification of KasA as the cellular target of an anti-tubercular scaffold.

• DOI: 10.1038/ncomms12581
• 发表时间: 2016-09-01
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Abrahams, Katherine A.;Chung, Chun-wa;Ghidelli-Disse, Sonja;Rullas, Joaquin;Jose Rebollo-Lopez, Maria;Gurcha, Sudagar S.;Cox, Jonathan A. G.;Mendoza, Alfonso;Jimenez-Navarro, Elena;Santos Martinez-Martinez, Maria;Neu, Margarete;Shillings, Anthony;Homes, Paul;Argyrou, Argyrides;Casanueva, Ruth;Loman, Nicholas J.;Moynihan, Patrick J.;Lelievre, Joel;Selenski, Carolyn;Axtman, Matthew;Kremer, Laurent;Bantscheff, Marcus;Angulo-Barturen, Inigo;Cacho Izquierdo, Monica;Cammack, Nicholas C.;Drewes, Gerard;Ballell, Lluis;Barros, David;Besra, Gurdyal S.;Bates, Robert H.
• 通讯作者: Bates, Robert H.