Abstract
Bioactive chemicals produced by microorganisms isolated from nature have been the source of most antibiotics in medical use today. However, many antibiotics are currently losing their potency due to rapidly spreading antibiotic resistance among pathogenic bacteria. Coincidently, very few new antibiotics have recently reached the market, essentially due to a very high re-discovery rate, compromising interest of major pharmaceutical companies to invest in the field. New strategies and technologies that allow targeted discovery of novel bioactive chemistry from yet underexplored natural resources may secure treatment options of life-threatening bacterial infections in the future.
In the joint frame of European research project SYSTERACT and Norwegian national research project INBioPharm, we are developing and integrating a suite of new technologies that will allow for a more efficient discovery of novel bioactive natural products with improved prospects for clinical use. A unique national collection of marine microorganisms at SINTEF/NTNU, Norway, is used as a platform for the development of bioinformatics, molecular biology, analytical, screening, and integrated systems biology methods to more efficiently access and exploit the huge potential of microorganisms for natural product biosynthesis. Central to this effort are the development of high throughput technologies for cloning (meta)genome derived biosynthetic gene clusters (BGCs) and their transfer between species for heterologous expression. Strains of the model Actinobacterium Streptomyces coelicolor are further developed into improved microbial cell factories to heterologously produce diverse bioactive compounds in amounts needed for structural and functional evaluation. Unprecedented systems biology understanding of S. coelicolor is being combined with morphology engineering and improved (de )regulation and precursor supply to accelerate bioactive compound discovery efforts. The new BGC cloning, transfer, and expression technologies provide access to both cryptic gene clusters of cultivable strains and the vast resources of otherwise inaccessible BGC functions from the vast majority of bacteria that cannot readily be cultivated in the laboratory.
The work presented was performed in the project INBioPharm funded by the Research Council of Norway (grant no. 248885) and the SYSTERACT project by ERASysAPP partner funding agencies in Norway, Germany, Netherlands and Sweden.
In the joint frame of European research project SYSTERACT and Norwegian national research project INBioPharm, we are developing and integrating a suite of new technologies that will allow for a more efficient discovery of novel bioactive natural products with improved prospects for clinical use. A unique national collection of marine microorganisms at SINTEF/NTNU, Norway, is used as a platform for the development of bioinformatics, molecular biology, analytical, screening, and integrated systems biology methods to more efficiently access and exploit the huge potential of microorganisms for natural product biosynthesis. Central to this effort are the development of high throughput technologies for cloning (meta)genome derived biosynthetic gene clusters (BGCs) and their transfer between species for heterologous expression. Strains of the model Actinobacterium Streptomyces coelicolor are further developed into improved microbial cell factories to heterologously produce diverse bioactive compounds in amounts needed for structural and functional evaluation. Unprecedented systems biology understanding of S. coelicolor is being combined with morphology engineering and improved (de )regulation and precursor supply to accelerate bioactive compound discovery efforts. The new BGC cloning, transfer, and expression technologies provide access to both cryptic gene clusters of cultivable strains and the vast resources of otherwise inaccessible BGC functions from the vast majority of bacteria that cannot readily be cultivated in the laboratory.
The work presented was performed in the project INBioPharm funded by the Research Council of Norway (grant no. 248885) and the SYSTERACT project by ERASysAPP partner funding agencies in Norway, Germany, Netherlands and Sweden.
