Actinomycetes produce a wealth of important natural products, which play a pivotal role in modern drug-based therapy of various diseases. Recent whole-genome sequencing projects have revealed that the number of biosynthetic gene clusters significantly outnumbers the natural products produced by actinomycetes under laboratory conditions. Only a minority of biosynthetic gene clusters are expressed under known laboratory conditions. The major challenge in the field now is to exploit this untapped reservoir of potentially active and useful compounds. Using synthetic and system biology approaches we will access these so far unavailable natural products. The overall strategy of the EXPLOGEN project will be implemented through the activities of four different work packages. WP1. Synthetic biobricks. Construction of different synthetic biobricks, which can be mixed and matched to build the synthetic devices and systems in actinomycetes. Generation of streptomyces strains with minimized genomes. WP2. Systems biology. The metabolic reconstruction of Streptomyces albus and S. lividans and its simulation in order to deliver gene targets for knockouts and overexpression experiments. Predicted mutants should accumulate main precursors of natural products, particularly polyketides. WP3. Regulatory network identification. Using systematic in vivo transposon mutagenesis combined with GFP-based flow cytometry assay and gusA based screening, we will identify gene networks responsible for the regulation and silencing of natural product biosynthesis. WP4. Metabolic engineering of the hosts. Generation of S. albus and S. lividans hosts accumulating main precursors for the heterologous production of natural products. Heterologous expression of the aranciamycin, phenalinolactone, and two "cryptic" biosynthetic gene clusters in the developed hosts. The outcome of this project will be a new platform for the production of novel natural products including valuable pharmaceuticals.
Start date: 01-01-2012 End date: 31-12-2016 Duration: 60 months Project cost: 1484016 Euro Project Funding: 1484016 Euro Administrative Contact Person: Michael STRÄTZ (Dr)