A systems approach to understanding metabolic switching in Streptomyces coelicolor

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.

Genetic and physiological manipulations of Streptomyces are essential for new drug discovery and production development. Predictive manipulation of metabolism will not only help to increase production of existing antibiotics but will also facilitate combinatorial biosynthesis of antibiotic pathway enzymes to generate novel secondary metabolites and provide new opportunities for the expression of hitherto cryptic secondary metabolite pathways. The main aim of the project is to facilitate integration and coordination of theoretical and experimental work elucidating metabolic regulation in a complex oligotroph Streptomyces coelicolor. A working model of the transition from primary to secondary phases of metabolism will be produced, interfacing growth related processes with non-growth linked productivity. The proposal consists of 7 work packages (WPs), WP 1, 4, and 7 (project 1) will be done at Warwick and WP6 at Aberdeen, the remaining WPs are part of the transnational component based in Norway, Germany, Netherlands and Spain. WP 1 is co-ordination and provision of real time PCR, programs for Qiagen BioRobot Universal and its application to the project work. WP 4 will conduct gene network inference, analysis and data integration of metabolic reprogramming and WP 7 encompasses analysis of global carbon (project 1), nitrogen and phosphate regulation: the central pathways of assimilation in Streptomyces coelicolor. Only Project 1 (the pathways of carbon assimilation during transitioantibiotic production on the level of the systemn phase and anaplerosis) of WP7 will be done at Warwick. Transcriptomics (WP5), proteomics (WP6), and metabolomics (WP2; provision of cell pastes and metabolomics, WP3 metabolic flux analysis and computational modelling of metabolism) each provide a different view on the organism's response to a changing environment, we will integrate these datasets into a consistent view of the key players for antibiotic production at the system level.