Methods and Means for Metabolic Engineering and Improved Product Formation by Micro-organisms

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This invention provides innovative methods and tools for metabolic engineering in microorganisms, particularly filamentous microorganisms and low G+C gram-positive bacteria such as Streptomyces, Bacillus, and Listeria. The core of the invention is the discovery that the protein DasR and its specific DNA binding sites (dre sites) act as a universal and powerful regulatory 'master switch' to control gene expression networks involved in metabolism, product formation (such as antibiotics and enzymes), and growth characteristics. By modulating the activity of DasR or its binding sites—either genetically, through small molecules, or by external inducers like N-acetylglucosamine—one can upregulate or downregulate the production of desired or undesired products (including secondary metabolites, enzymes, and antibiotics) in industrially important microorganisms.

Use CasesContent extracted from patent full text and abstract with AI.

• Enhancing production of antibiotics and other secondary metabolites in industrial fermentation processes.
• Activating cryptic gene clusters in microorganisms to discover and manufacture new drugs, including anti-cancer and antifungal compounds.
• Boosting yield of valuable enzymes (e.g., chitinases, amylases, cellulases, lipases) used in food, feed, biofuel, and chemical industries.
• Reducing formation of unwanted side products or metabolic shunt products during microbial fermentation.
• Regulating and improving protein secretion and folding for the manufacture of recombinant proteins.
• Controlling sugar and metabolite uptake efficiency for more effective bioprocessing.
• Engineering microorganisms with altered growth, morphology, or branching to optimize large-scale fermentation.
• Fine-tuning metabolic pathways (e.g., glycolysis, amino acid biosynthesis) to redirect cellular resources towards target products.

BenefitsContent extracted from patent full text and abstract with AI.

• Universal applicability across a wide range of industrially relevant microorganisms, both naturally occurring and engineered.
• Non-invasive control options—such as addition of small molecule inducers (e.g., N-acetylglucosamine)—allow metabolic pathway modulation without the need for complex genetic modifications.
• Precise upregulation or downregulation of product formation, increasing efficiency, selectivity, and yield.
• Unlocks previously silent (cryptic) gene clusters, enabling discovery of new bioactive compounds and natural products.
• Ability to reduce harmful or unwanted byproducts, improving product purity and simplifying downstream processing.
• Facilitates rational design of metabolic pathways, helping to innovate new microbial strains for industrial biotechnology applications.
• Supports improved secretion and folding of proteins, vital for biopharmaceutical manufacturing.
• Potential to enhance the economic sustainability and scalability of bioprocessing due to increased productivity and targeted pathway control.

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Patent Abstract

The invention relates to the field of biochemistry, molecular biology and microbiology. More specific the invention relates to methods and means for metabolic engineering and improved product formation by a filamentous micro-organism or a low G+C gram-positive bacterium. The invention discloses that DasR and DasR binding sites play an important and universal role in the control of gene expression in microorganisms Based on this finding, the invention provides multiple useful applications, such as a method for regulating the expression of a gene of interest, a method for controlling metabolism, a method for decreasing undesired expression and many more. Moreover, the invention also provides means that can be used to establish said methods: for example a micro-organism in which the DasR binding site in operable linkage with a particular gene has been modified to obtain increased or decreased expression of a protein (being a desired or undesired protein) encoded by said gene.