There is an urgent need to develop new drugs to combat antibiotic resistance. The solution can be surprisingly close, in microorganisms living in the Trondheim fjord.
Project lead: Alexander Wentzel
Partners: NTNU, Auburn University, Varigen Biosciences Corp., Jacobs University Bremen, Wageningen University, Leiden University and University of Tübingen
Funding: NOK 27.6 mill.
Genes from marine microorganisms as a source for new drugs
Scientists in Trondheim are currently investigating thousands of microorganisms from fjord sediments and marine sponges, hunting for gene clusters that can be used to make new chemicals with antibiotic properties.
The most interesting gene clusters will be copied of the microorganism where they are found and transferred to a host organism that is easier to grow and control. The new host will produce larger amounts of the chemicals, making it possible to detect activities of the synthesized compounds and evaluate their potential as drug candidates.
The same method can be used to find compounds with anti-cancer properties.
Most antibiotics used today are molecules isolated from microorganisms found on land, mainly bacteria and fungi. An excessive use of antibiotics has led to the rise of pathogenic bacteria that are multi-resistant, which can render otherwise easily curable infections again life threatening. The development of new antibiotics is currently too slow to keep up with the development of resistance. One of the reasons for that is that the same antibiotics are discovered repeatedly from similar organisms.
The marine environment is less studied than the terrestrial, and scientists foresee great opportunities to find completely new bioactive compounds. One additional advantage in the project is the development and use of specialized host organisms to produce compounds from isolated gene clusters.
The project is complex and highly interdisciplinary, which demands a close collaboration between experts in microbiology, molecular biology, systems biology, synthetic biology, bioinformatics, mathematics and chemistry, mutually understanding each other’s fields.
The project is coordinated and run by SINTEF Materials and Chemistry, in close collaboration with NTNU and international partners from USA, Germany and Netherlands.
More about the project
Searching among 50 000 gene clusters to find those that encode new drugs
The project INBioPharm - Integrated Novel Natural Product Discovery and Production Platform for Accelerated Biopharmaceutical Innovation from Microbial Biodiversity will develop a new technology platform that will make it possible to discover new bioactive compounds faster and more efficiently. Compounds that can be used to produce new medicines.
The research environments at SINTEF and NTNU have a long standing experience in retrieving marine microorganisms from the Trondheim fjord and to explore their properties. They have a large collection of several thousands of microbes from the sediments of the fjord and from sponges living there. The scientists expect that many of them have the potential to produce new compounds for medical use.
Hunting for silent genes
One challenge is that many of the microbes isolated produce such small amounts of the interesting compounds that they are barely measurable, even by using the most sensitive methods. The scientists must therefore take a detour to find and characterize new bioactive compounds.
For each microbe they need to identify the silent gene clusters that encodes the production of potentially medically interesting compounds.The gene clusters are then cut out and transferred to a host microorganism that is capable of activating the genes and produce large enough amounts of bioactive compounds for scientists to test their possible use as medicine. A particularly suitable host is the well-studied Actinobacterium Streptomyces coelicolor. In the project, this bacterium will be developed into a cell factory that can produce efficiently bioactive compounds based on a large number of different gene clusters from marine microorganisms.
Massive production of data
Today’s technologies make it easy to read the genome (DNA) in any microorganism, leading to the amounts of data being produced massively expanding. In earlier projects, scientists at SINTEF have sequenced the genomes of about one thousand bacteria from the biobank of isolates. Each bacterium has between 20-50 different gene clusters, and each cluster encodes a potentially interesting compound. To reduce the number of gene clusters to investigate in detail, the scientists will use bioinformatics and mathematical modeling to find the clusters that are most interesting for synthesizing novel compounds with medical potential.
Two collaborators in USA are assisting on the technology used to transfer gene clusters from one microbe to another. This is a demanding procedure that needs to be repeated for all interesting gene clusters. An important part of the project is therefore to develop robotized procedures to make the transfer more efficient.
When the gene cluster is transferred to the host, it will in principle be able to produce the compounds, even though still a large number of clusters will not be activated in this way.
Focusing on the best
Mass spectrometry is an important technology to evaluate if the new compound is in fact produced in higher amounts in the host than in the original bacterium. Each of the compounds produced will be tested for different types of bio-activity, particularly towards pathogenic bacteria and fungi, and cancer cells. For this, a robotized screening platform developed at SINTEF is applied. To expand further the possibility of positive hits, each gene cluster will be transferred to several host species and tested for production of compounds.
At this step scientists are left with a range of bioactive compounds from different host organisms. The most interesting ones are put through a chemical analysis by mass spectrometry to evaluate if the compounds are new and have a novel chemical structure. Much of the evaluation can be performed even throughout the workflow, by integrating the mass spectrometry data and the bioinformatic analysis of the gene clusters from the marine microbes and by comparing them to the structures of already known antibiotics. In this way the work early focus on the most promising compounds. An analysis platform like this will make it possible to exploit the large potential of genes from natural microorganisms in a faster and more targeted way.
The INBioPharm project depends on experts in microbiology, molecular biology, systems biology, bioinformatics, mathematics and chemistry working together and understanding each other.
For a physicist with no background in biology, it will take some time to understand what the microbiologists and geneticists are talking about. And vice versa; for microbiologists to understand about systems biology and mathematical modeling.
The most central scientists in the project are co-located at SINTEF and NTNU in Trondheim and even share labs there. The short distance makes it possible for the scientists to meat frequently and informally at the coffee machine and on the corridor, and this makes it easier to visit a colleague spontaneously. In addition, the project staff meets on a regular basis in project meetings where they present and discuss results.
Scientists from Trondheim are also traveling to collaborators abroad where they spend several weeks to learn new technology and to analyse data. The project collaborates with research groups in Germany and Netherlands to investigate which of the thousands of bacterial strains have the largest potential to make interesting compounds, and with researchers in USA on the technology of transferring gene clusters. The external partners participate regularly on Skype-meetings.
The project has two PhD students and one post doc that all are working at SINTEF or NTNU.
Responsible research and innovation (RRI)
The project is highly relevant in a societal perspective and is in close dialog with the networking project on RRI aspects. A workshop is planned to address aspects such as: How can new ways of discovering antibiotics be part of the solution to antibiotic resistance? Who should own the results from the research on new antibiotics? And who should pay for the development of new drugs if the pharmaceutical companies are not interested?
The research in the project is performed in approved facilities to ensure that the modified bacteria are not released into nature.
The bacterial strains that the scientists are working on will contain interesting compounds that can potentially become new drugs. The goal is to find new compounds with interesting activities and beneficial properties that the industry can develop further. Norwegian pharmaceutical companies are therefore represented in the steering committee of the project.
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