BaSynthec will combine computational and experimental biology approaches with novel high-throughput methodologies to reduce and modify à la carte the chromosome of Bacillus subtilis, a genetically tractable bacterium and one of the key microbes used as a Cell Factory in biotechnology. Simpler B. subtilis strains with reduced energy consumption for self maintenance will be designed and constructed by removing some potentially expensive cellular processes. The cells with the lowest experimentally determined waste of energy and with industrially relevant phenotypes will be engineered to reroute the flux devoted to biomass formation through rational modifications of the complex metabolic regulations, and will be used as biotechnological platforms to plug in synthetic modules. For this purpose, BaSynthec will develop a model-driven approach to design and engineer the strains with predetermined features, with a particular focus on unrestricted metabolic activity and the plug-in of synthetic functional modules. This strategy is based on the recent development of two complementary modelling approaches for B. subtilis: i) a genome-scale model of genetic and metabolic regulatory networks associated with a novel method called “Resource Balance Analysis” defining the formal background of model-based approaches for engineering strains; and ii) the development of a new genome-scale metabolic model of B. subtilis which is the most complete and accurate that exists today. Two pathways of high biotechnological relevance will be used for establishing the proof-of-principle of the assembly of functional synthetic modules: i) the vitamin B5 biosynthetic pathway, and ii) the secretion machinery for the export of extra-cellular enzymes. It is anticipated that validated simpler bacterial strains together with the modelling framework generated by BaSynthec will be used as generic biotechnological platforms to better control and exploit cell metabolism in industrial processes.
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