A systems approach to understanding metabolic switching in Streptomyces coelicolor

理解天蓝色链霉菌代谢转换的系统方法

• 批准号: BB/F003439/1
• 负责人: Margaret Smith
• 金额: $ 41.27万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF003439%2F1
• 关键词: systems; approach; understanding; metabolic; switching

Bacteria found in soil have been exploited for their ability to produce antibiotics for over 60 years. This resulted in the effective treatment of diseases such as TB, bacterial pneumonia, sepsis and a wide range of infections which previously resulted in death or had a very low survival rate. Recently the alarming rise in antibiotic resistant pathogens especially those acquired in hospitals has reduced the efficacy of our existing armoury of drugs and new antibiotics are badly needed. In addition there are a number of emerging pathogens for which existing drugs are not effective. Antibiotics are made during the second phase of growth when there is a transition in metabolism from primary metabolism to secondary metabolism. Primary metabolism is growth related and involves all the normal cellular activities associated with cell growth and division. Whereas secondary metabolism is non-growth linked and is non-essential but many important activities occur during this phase which help the bacterium survive and compete in its natural environment. One of these activities is antibiotic production and is widespread in streptomycetes found in most soils. These bacteria have a fascinating life history and are abundant producers of biologically active compounds many of which have been exploited for their anti-tumour, anti-bacteria and anti-fungal activity. Our research will greatly improve our understanding of how these bacteria regulate the transitions from primary to secondary metabolism and provide mathematical models to simulate the metabolic switch of life styles. The overall approach is regarded as a 'systems' analysis where a model is built of the whole metabolism and it can predict outcomes that will not have been determined previously by experimental methods. A range of modelling tools will be provided and these will be available for use with many other projects involved in a systems approach to biology. The fuller understanding of the metabolic switch and the elucidation of how and why certain antibiotics are made under defined growth conditions will be vital for the full exploitation of these bacteria. Many tools are available to manipulate bacterial genomes and with an understanding of the metabolism it will be possible to discover and manipulate growth in order to produce novel antibiotics.

60多年来，人们一直利用土壤中的细菌生产抗生素。这导致结核病、细菌性肺炎、败血症和各种感染等疾病得到有效治疗，这些疾病以前会导致死亡或生存率极低。最近，抗生素耐药病原体的惊人增长，特别是在医院获得的耐药病原体，降低了我们现有药物的效力，迫切需要新的抗生素。此外，还有一些新出现的病原体，现有药物对它们无效。抗生素是在生长的第二阶段产生的，此时新陈代谢从初级代谢过渡到次级代谢。初级代谢与生长有关，包括与细胞生长和分裂有关的所有正常细胞活动。虽然次级代谢与生长无关，也不是必需的，但许多重要的活动发生在这一阶段，这些活动有助于细菌在自然环境中生存和竞争。这些活动之一是抗生素的生产，在大多数土壤中发现的链菌中广泛存在。这些细菌有一个迷人的生活史，是丰富的生物活性化合物的生产者，其中许多已被开发用于抗肿瘤，抗菌和抗真菌活性。我们的研究将大大提高我们对这些细菌如何调节从初级代谢到次级代谢的转变的理解，并提供数学模型来模拟生活方式的代谢转换。整体方法被认为是一种“系统”分析，其中建立了整个代谢的模型，并且可以预测以前通过实验方法无法确定的结果。将提供一系列建模工具，这些工具将可用于涉及生物学系统方法的许多其他项目。更充分地了解代谢开关，阐明某些抗生素是如何以及为什么在特定的生长条件下产生的，对于充分利用这些细菌至关重要。有许多工具可用于操纵细菌基因组，并且随着对代谢的了解，将有可能发现和操纵生长以生产新型抗生素。

项目成果

The mechanism of patellamide macrocyclization revealed by the characterization of the PatG macrocyclase domain.

• DOI: 10.1038/nsmb.2340
• 发表时间: 2012-08
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Koehnke, Jesko;Bent, Andrew;Houssen, Wael E.;Zollman, David;Morawitz, Falk;Shirran, Sally;Vendome, Jeremie;Nneoyiegbe, Ada F.;Trembleau, Laurent;Botting, Catherine H.;Smith, Margaret C. M.;Jaspars, Marcel;Naismith, James H.
• 通讯作者: Naismith, James H.

The dynamic architecture of the metabolic switch in Streptomyces coelicolor.

• DOI: 10.1186/1471-2164-11-10
• 发表时间: 2010-01-06
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Nieselt K;Battke F;Herbig A;Bruheim P;Wentzel A;Jakobsen ØM;Sletta H;Alam MT;Merlo ME;Moore J;Omara WA;Morrissey ER;Juarez-Hermosillo MA;Rodríguez-García A;Nentwich M;Thomas L;Iqbal M;Legaie R;Gaze WH;Challis GL;Jansen RC;Dijkhuizen L;Rand DA;Wild DL;Bonin M;Reuther J;Wohlleben W;Smith MC;Burroughs NJ;Martín JF;Hodgson DA;Takano E;Breitling R;Ellingsen TE;Wellington EM
• 通讯作者: Wellington EM