DL: Integrated Novel Natural Product Discovery & Production Platform for Accelerated Biopharm Innovation from Microbial Biodiversity

As part of the Centre for Digital Life Norway (DLN), the research project INBioPharm developed a new technology platform that enables a more efficient discovery of new bioactive molecules from microbes in nature with the potential to become future medicine. The technology developments built on more than 1200 marine bacterial strains from a unique strain collection at SINTEF/NTNU with the genetic potential to produce several ten thousand compounds of which several may have a new antibiotic function. Advanced bioinformatics analysis of the strains' genome sequences in collaboration with partners in Netherlands and Germany identified the 88 most promising strains for further work in the project. A new type of cloning technology was applied in collaboration with partners in USA to capture the genetic basis of 30 of these compounds in a targeted way and transfer it into a series of unique bacterial host strains capable of their production. INBioPharm studied and further developed the well-studied soil bacterium Streptomyces coelicolor for that purpose. New mathematical models of this bacterial species and new bioinformatics tools were developed and applied in the project to guide its further genetic improvement with respect to the synthesis of new bioactive compounds. Strain development was conducted in close collaboration with partners of the European ERA-SysAPP project SYSTERACT. In addition, advanced data integration methods were developed that allow a quicker evaluation of the production of entirely new bioactive compounds with basis in the marine genetic material. One such compound with antimicrobial activity and a new chemical structure was ultimately discovered, clearly showing the strength and functionality of the INBioPharm biodiscovery platform. The INBioPharm project has also during its final phase been a visible and active part of DLN and participated in discussions on the societal challenges representing the basis for its research, as well as the potential of microbial biodiversity for medical and sustainable benefits to society.

The spectrum of impacts of the INBioPharm project and its results is diverse and of relevance for a broad range of different stakeholders. It provided the participating project partners and collaborators with a unique opportunity to systematically work together on implementing a new technology platform that enables a more efficient utilization of microbial biodiversity to discover new bioactive compounds with medical application potential. This serves, among others, the pressing need of finding new antibiotics that secure efficient treatment of infections with multi-resistant human pathogens in the future. In addition, it demonstrates that interdisciplinary approaches can lead to new solutions in biotechnology and bioprospecting that can be attractive for pharmaceutical industry to adopt and apply on own biodiversity resources, including in collaboration with research partners. Through that, accelerated biopharmaceutical innovation is ensured, with expected benefit for society.

Rapid discovery of novel bioactive natural products from microbial biodiversity as the basis for new pharmaceutical products will be a key in solving the societal challenges of antimicrobial resistance and deadly diseases, like cancer. The INBioPharm project will provide a new, generic platform for the more efficient discovery and production of novel bioactive compounds with high medical application potential from natural biodiversity. A significantly lower rate of re-discovery of known, and more efficient methods towards novel pharmaceutical compounds will be the basis for accelerated innovation on the biopharmaceutical market. The unique national collection of marine Actino¬mycete strains at SINTEF/NTNU will be used as a validated basis to systematically fill in the technology gaps towards this aim. State-of-the-art functional metagenomics, advanced chemical analytics, systems biology and synthetic biology technology, and high throughput bioactivity screening will be integrated in a highly interdisciplinary way by our team of renowned national and international experts in all relevant fields. Central achievements of INBioPharm will be i) Systems Biology optimized Streptomyces coelicolor Superhost strains for an improved success rate in heterologous production of novel bioactive compounds, ii) more efficient Functional Metagenomics tools for long-insert BAC library cloning, sequencing and parallelized transfer to multiple expression hosts, iii) high throughput/high resolution mass spectrometry analysis for novel compound detection, as well as iv) more reliable prediction of compound novelty based on integration of multiple types of analysis data. Already during the project, a large number of new gene clusters from Norwegian marine microorganisms will be discovered and characterized with respect to the production of potentially novel compounds with anti-microbial and anti-cancer activity, thus demonstrating the capabilities of the INBioPharm platform.