A systems approach to understanding metabolic switching in Streptomyces coelicolor

在土壤中发现的细菌因其产生抗生素的能力而被开发了60多年。这导致了对结核病、细菌性肺炎、败血症等疾病的有效治疗，以及以前导致死亡或存活率非常低的各种感染。最近，抗药性病原体的惊人增长，特别是在医院获得的病原体，降低了我们现有药物武库的效力，迫切需要新的抗生素。此外，还有一些新出现的病原体，现有的药物对其无效。抗生素是在生长的第二阶段制造的，此时新陈代谢从初级新陈代谢过渡到次级新陈代谢。初级代谢与生长有关，涉及与细胞生长和分裂相关的所有正常细胞活动。虽然次生代谢不是与生长相关的，也不是必需的，但在这个阶段发生了许多重要的活动，帮助细菌在其自然环境中生存和竞争。这些活动之一是产生抗生素，在大多数土壤中发现的链霉菌中广泛存在。这些细菌有着令人着迷的生活史，是生物活性化合物的丰富生产者，其中许多化合物已被开发用于抗肿瘤、抗细菌和抗真菌活性。我们的研究将极大地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，并为模拟生活方式的代谢转换提供数学模型。整体方法被认为是一种“系统”分析，其中建立了一个关于整个新陈代谢的模型，它可以预测以前无法通过实验方法确定的结果。将提供一系列建模工具，这些工具将与许多其他涉及生物学系统方法的项目一起使用。更充分地了解代谢开关，并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。有许多工具可以用来操纵细菌基因组，了解了新陈代谢，就有可能发现和操纵生长，以生产新的抗生素。

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.