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BIOTEK2021-Bioteknologi for verdiskaping

ERA-NET: Systematic Rebuilding of Actinomycetes for Natural Product Formation

Awarded: NOK 6.0 mill.

There is an urgent need for new antibiotics to fight life-threatening bacterial infections and counteract the increasing problem of antibiotic resistance. New sequencing technologies and bioinformatics methods have provided deep insight into the enormous unexploited genetic pool and potential of environmental microbial biodiversity to synthesize entirely new bioactive compounds. However, more efficient tools for new antibiotic discovery and production are needed to more efficiently bringing new antibiotics into development and quicker on the market. The ERA-SysAPP project SYSTERACT (2015-2019) brought together six research partners from Norway, Germany, Netherlands and Sweden to address this issue in a transnational effort to develop the model actinobacterium Streptomyces coelicolor into a 'Superhost' for the efficient production of bioactive compounds from introduced foreign microbial DNA and as a powerful tool in bioprospecting for new antibiotics. Central to this effort was the application of Systems Biology, combining microbiology, genetics, biochemistry and fermentation technology, with modelling, which should lead to a better description and understanding of S. coelicolor as a complex biological system and enabling its targeted improvement for uses in antibiotics discovery and production. The project built and expanded on the comprehensive expertise acquired in the previous ERA-Net SysMO project STREAM, as well as existing Streptomyces coelicolor strains available in the consortium. The best suited basis strains were used for the generation of omics data at different metabolic levels as an input to improving existing metabolic models available for S. coelicolor from previous work. Predictions from these models, as well as parallel work in the project on mycelial morphology, precursor metabolite supply and nitrogen metabolism provided input and guidance to targeted strain engineering efforts, successively improving the production of selected model antibiotics from respective model gene clusters introduced into these strains. The resulting strains were characterized with respect to their capabilities to better produce the model antibiotics. Beneficial modifications were combined, ultimately resulting in a panel of S. coelicolor strains with 1-3 additional genetic changes compared to the pre-developed original strains. At the end of the project, the most advanced SYSTERACT 'Superhost' strains have a significantly improved morphology for a better handling in bioreactors, are improved in providing the most important precursors for the production of members of the class of polyketide antibiotics, and/or are modified in their nitrogen metabolism with observable positive effects on model antibiotics production. The SYSTERACT panel of S. coelicolor strains is now, at the end of 2019 subject to further detailed evaluation of their capabilities to produce entirely new bioactive compounds from biosynthetic gene clusters with unknown function, as well as further strain optimization in the frame of ongoing other projects with involvement of SYSTERACT partners.

ERA-SysAPP-prosjektet SYSTERACT har gitt SINTEF og de andre forskningspartnerne muligheten til å bygge systematisk og fokusert videre på det tidligere systembiologiprosjektet på S. coelicolor, SysMO STREAM, utvide det tverrfaglige, internasjonale samarbeidet, utbygge den gjensidige forståelsen av modellerere og eksperimetalister, og posisjonere partnerne i lag som ledende i Europa på S. coelicolor systembiologi og stammeutvikling. Prosjektresultatene viser en ny vei og vil være et sentralt verktøy for eksempel mot nye antibiotika fra mikrobielle (meta)genomer med potensialet for et viktig bidrag til å sikre tilgang til effektive antibiotika også i fremtiden. De nye metabolske modellene, optimerte vertsstammene og den samlede kunnskapen på S. coelicolor utviklet i SYSTERACT-prosjektet vil være viktige bidrag fra SYSTERACT-partnerne inn i nye prosjekter på nasjonalt og internasjonalt nivå, både innen grunn- og anvendt forskning, og mot bioteknologisk og farmasøytisk industri.

There is an urgent need for novel antibiotics to fight life-threatening infections and to counteract the increasing problem of antibiotic resistance. New molecular genetic and biochemical tools have provided insight into the enormous unexploited genetic pool of environmental microbial biodiversity for the synthesis of potential new bioactive compounds. However, efficient tools for new antibiotic discovery and production are needed to more efficiently bringing new antibiotics to market. The SYSTERACT project brings together six partners from four ERA-SysApp member countries in an international effort to develop the model actinomycete Streptomyces coelicolor into a 'Superhost' for the efficient heterologous production of bioactive compounds. Central to this approach will be an iterative Systems Biology process, combining microbiology, genetics, biochemistry, and fermentation technology with modelling. The project will build on and utilize the comprehensive expertise, data and models acquired in the ERA-Net SysMO project STREAM, as well as existing Streptomyces coelicolor strains available in the consortium. In three subsequent stages, SYSTERACT will improve existing basic metabolic and gene regulatory models available for S. coelicolor from previous work, and use these for predictions to successively improve model antibiotic gene clusters carrying strains with respect to their antibiotic production capabilities. In turn, new experimental data acquired will be used to further improve the prediction potential of the refined models. By that means, we aim to generate a stepwise improved 'Superhost' for the production of antibiotics in which metabolic bottlenecks and regulatory restriction are greatly mitigated. The optimized strains will be tested concerning their applicability for an improved production of commercially relevant antibiotics and the expression of novel bioactive gene clusters identified in new actinomycete strains and environmental metagenomes.

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BIOTEK2021-Bioteknologi for verdiskaping