Defining the metabolic phenotype of intracellular Mycobacterium tuberculosis

定义细胞内结核分枝杆菌的代谢表型

• 批准号: MR/K01224X/1
• 负责人: Dany Beste
• 金额: $ 50.15万
• 依托单位: University of Surrey
• 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%2FK01224X%2F1
• 关键词: Defining; metabolic; phenotype; intracellular; Mycobacterium

Tuberculosis (TB) is a disease which plagued ancient Egyptians and is still one of the most significant human diseases thousands of years later. A key to the success of Mycobacterium tuberculosis, the bacterium which causes TB is the ability to survive and grow in white blood cells, the very cells which are equipped to eliminate bacteria from the body. In order to do this M. tuberculosis must be able to acquire nutrients and energy from this isolated niche. Several studies have highlighted that targeting nutrient utilisation as a potentially productive route for drug development yet the nutrients consumed by intracellular M. tuberculosis are currently unknown. The aim of this project is to use labelled nutrient sources to directly measure the metabolism of M. tuberculosis growing in white blood cells. This research will allow us to identify the major energy (carbon) source consumed by M. tuberculosis in the host cell. We will also in parallel investigate the metabolism of M. tuberculosis in defined environmental conditions in the laboratory in order to establish the metabolic pathways used to break down different combinations of nutrients that have been identified as being consumed intracellularly. All of the data will be incorporated into mathematical models of TB in order to generate a reconstruction of the intracellular metabolism of this pathogen. This information will be vitally important for new drug and vaccine development, as well as advancing our knowledge of the pathogenesis of this globally important pathogen.

结核病（TB）是一种困扰古埃及人的疾病，数千年后仍然是最重要的人类疾病之一。结核分枝杆菌成功的一个关键是，导致结核病的细菌能够在白色血细胞中生存和生长，而这些细胞正是用来消除体内细菌的。为了做到这一点M。结核病必须能够从这个孤立的小生境中获得营养和能量。一些研究强调，靶向营养利用作为药物开发的潜在生产途径，但细胞内M。结核病目前尚不清楚。本项目的目的是利用标记的营养源直接测量M.长在白色血细胞中的结核病。这项研究将使我们能够确定的主要能源（碳）源消耗的M。结核病在宿主细胞我们还将同时研究M的代谢。在实验室中在限定的环境条件下对结核病进行研究，以建立用于分解已被确定为在细胞内消耗的营养素的不同组合的代谢途径。所有的数据将被纳入结核病的数学模型，以产生这种病原体的细胞内代谢的重建。这些信息对于新药和疫苗的开发以及推进我们对这种全球重要病原体的发病机制的了解至关重要。

项目成果

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

• DOI: 10.1038/s41467-020-19959-4
• 发表时间: 2020-11-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mackenzie JS;Lamprecht DA;Asmal R;Adamson JH;Borah K;Beste DJV;Lee BS;Pethe K;Rousseau S;Krieger I;Sacchettini JC;Glasgow JN;Steyn AJC
• 通讯作者: Steyn AJC

The anaplerotic node is essential for the intracellular survival of Mycobacterium tuberculosis.

• DOI: 10.1074/jbc.ra118.001839
• 发表时间: 2018-04-13
• 期刊: The Journal of biological chemistry
• 作者: Basu P;Sandhu N;Bhatt A;Singh A;Balhana R;Gobe I;Crowhurst NA;Mendum TA;Gao L;Ward JL;Beale MH;McFadden J;Beste DJV
• 通讯作者: Beste DJV

Structural and molecular dynamics of Mycobacterium tuberculosis malic enzyme, a potential anti-TB drug target

• DOI: 10.1101/2020.07.07.192161
• 发表时间: 2020-07
• 期刊: bioRxiv
• 作者: K. Burley;B. Cuthbert;Piyali Basu;J. Newcombe;E. M. Irimpan;Robert Quechol;Ilona P. Foik;D. Mobley;D. Beste;C. Goulding

Metabolic fluxes for nutritional flexibility of Mycobacterium tuberculosis.

• DOI: 10.15252/msb.202110280
• 发表时间: 2021-05
• 期刊: Molecular systems biology
• 影响因子: 9.9
• 作者: Borah K;Mendum TA;Hawkins ND;Ward JL;Beale MH;Larrouy-Maumus G;Bhatt A;Moulin M;Haertlein M;Strohmeier G;Pichler H;Forsyth VT;Noack S;Goulding CW;McFadden J;Beste DJV
• 通讯作者: Beste DJV

Dual RNA Sequencing of Mycobacterium tuberculosis-Infected Human Splenic Macrophages Reveals a Strain-Dependent Host-Pathogen Response to Infection.

• DOI: 10.3390/ijms23031803
• 发表时间: 2022-02-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: López-Agudelo VA;Baena A;Barrera V;Cabarcas F;Alzate JF;Beste DJV;Ríos-Estepa R;Barrera LF
• 通讯作者: Barrera LF