Construction of a genome scale metabolic model of Mycobacterium tuberculosis to investigate growth-regulated modulation of metabolism.

构建结核分枝杆菌基因组规模的代谢模型，以研究代谢的生长调节。

• 批准号: BB/D007208/1
• 负责人: Johnjoe McFadden
• 金额: $ 55.53万
• 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: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD007208%2F1
• 关键词: Construction; genome; scale; metabolic; model

The TB bacillus is an important pathogen of man and animals that kills about three million people each year. This proposal is to develop a virtual model of the BCG vaccine strain of the TB bacillus in a computer. The model will provide important insight into how this pathogen grows and replicates. The model may also be used to perform virtual experiments that would be very hard or impossible to perform in the real world. For instance, it is difficult to study the behaviour of the TB bacillus when it is growing inside patient's lungs. But if we can identify the metabolic pathways that are active then we can perform easily virtual experiments that will, for instance, investigate how the bacillus will respond to a new antibiotic whilst it is living in the patient's lungs. The virtual TB may also be used to screen new compounds for activity against the TB bacillus: the effect of various antibiotics can be tested in the virtual TB cell far more quickly than with live cells (and with no possibility of the experimenter catching TB). But probably most importantly, the virtual TB cell can be used to invent new antibiotics, by identifying pathways, or groups of pathways, that are essential for growth. This model will first be built using DNA sequence data from the genome. However, to make the virtual cell more realistic, we must incorporate biological data. We will therefore grow the real life organism (actually the vaccine strain of the TB bacillus) in highly defined conditions in the laboratory and perform chemical analysis of what goes in and what comes out of the cell. A remarkable mathematical technique, known as metabolic flux analysis, can then be used to estimate the flux of metabolites through each central metabolism pathway inside the cell. This information will be incorporated into the virtual cell to make its behaviour correspond more closely with the biological organism. The next stage of the project is testing our virtual cell. To do this we will identify which pathways are essential in the virtual cell and then inactivate those pathways in living cells. We will then see if the growth (or absence of growth) of the real life cells matches the predictions of the model. These tests will be used to refine and improve the model that may thereafter be used in drug development.

结核杆菌是人类和动物的重要病原体，每年导致约三百万人死亡。该提案是在计算机中开发结核杆菌卡介苗疫苗株的虚拟模型。该模型将为了解这种病原体如何生长和复制提供重要的见解。该模型还可用于执行在现实世界中很难或不可能执行的虚拟实验。例如，很难研究结核杆菌在患者肺部生长时的行为。但是，如果我们能够识别活跃的代谢途径，那么我们就可以轻松地进行虚拟实验，例如，研究杆菌在患者肺部生存时对新抗生素的反应。虚拟结核病还可用于筛选针对结核杆菌活性的新化合物：可以在虚拟结核病细胞中比活细胞更快地测试各种抗生素的效果（并且实验者不可能感染结核病）。但也许最重要的是，通过识别生长所必需的途径或途径组，虚拟结核细胞可用于发明新的抗生素。该模型首先将使用基因组中的 DNA 序列数据构建。然而，为了使虚拟细胞更加真实，我们必须结合生物数据。因此，我们将在实验室的高度限定条件下培养现实生物体（实际上是结核杆菌的疫苗株），并对细胞中的进出物质进行化学分析。然后可以使用一种被称为代谢通量分析的卓越数学技术来估计通过细胞内每个中央代谢途径的代谢物通量。这些信息将被纳入虚拟细胞中，使其行为与生物有机体更加紧密地对应。该项目的下一阶段是测试我们的虚拟单元。为此，我们将确定哪些途径在虚拟细胞中至关重要，然后使活细胞中的这些途径失活。然后我们将查看现实细胞的生长（或不生长）是否与模型的预测相符。这些测试将用于完善和改进随后可用于药物开发的模型。

项目成果

System-level strategies for studying the metabolism of Mycobacterium tuberculosis.

研究结核分枝杆菌代谢的系统级策略。

• DOI: http://dx.10.1039/c003757p
• 发表时间: 2010
• 期刊: Molecular bioSystems
• 作者: Beste DJ

GSMN-TB: a web-based genome-scale network model of Mycobacterium tuberculosis metabolism.

GSMN-TB：基于网络的结核分枝杆菌代谢的基因组规模网络模型。

• DOI: http://dx.10.1186/gb-2007-8-5-r89
• 发表时间: 2007
• 期刊: Genome biology
• 影响因子: 12.3
• 作者: Beste DJ

Transcriptomic analysis identifies growth rate modulation as a component of the adaptation of mycobacteria to survival inside the macrophage.

转录组分析将生长速率调节确定为分枝杆菌适应巨噬细胞内生存的一个组成部分。

• DOI: http://dx.10.1128/jb.01787-06
• 发表时间: 2007
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Beste DJ

The genetic requirements for fast and slow growth in mycobacteria.

分枝杆菌快速和缓慢生长的遗传要求。

• DOI: http://dx.10.1371/journal.pone.0005349
• 发表时间: 2009
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Beste DJ

¹³C metabolic flux analysis identifies an unusual route for pyruvate dissimilation in mycobacteria which requires isocitrate lyase and carbon dioxide fixation.

C代谢流分析确定了分枝杆菌中丙酮酸异化的不寻常途径，该途径需要异柠檬酸裂解酶和二氧化碳固定。

• DOI: http://dx.10.1371/journal.ppat.1002091
• 发表时间: 2011
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Beste DJ