Unlocking New Potential in Natural Product Discovery Using CRISPR-Cas9 Technology
Natural products derived from bacteria have long been a rich source of antibiotics, anticancer agents, and other therapeutic compounds. However, the vast majority of these biosynthetic gene clusters (BGCs) remain "silent," meaning they are not actively expressed under standard laboratory conditions. This has created a significant challenge in unlocking their potential for drug discovery.
A groundbreaking study published in Science introduces a revolutionary CRISPR-Cas9-based approach to activate and amplify these hidden BGCs, accelerating the discovery of novel natural products.
The Challenge of Silent Biosynthetic Gene Clusters (BGCs)
Bacteria naturally produce a variety of bioactive compounds, encoded within their genomes in BGCs. However, many of these clusters are not expressed in the laboratory due to specific environmental triggers or the complexity of their regulation. This means their potential to produce valuable compounds remains untapped, limiting the pipeline for new antibiotics and other therapeutics.
The CRISPR-Cas9 Solution: ACTIMOT Technology
Researchers at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have developed an innovative technology called ACTIMOT (Advanced Cas9-mediaTed In vivo MObilization and mulTiplication of BGCs). This method leverages the power of CRISPR-Cas9 to overcome the challenges of silent BGCs by activating, amplifying, and transferring them for further analysis and compound production.
How ACTIMOT Works:
CRISPR-Cas9 Editing: Targeted editing is used to extract specific BGCs from the bacterial genome.
Insertion into Plasmids: The extracted BGCs are inserted into mobile genetic units, such as plasmids.
Activation and Amplification: The plasmids enable the expression and multiplication of BGCs, turning on the production of natural compounds.
Host Transfer: If the original host bacterium is not suitable for large-scale production, the plasmids can be transferred into other strains optimized for production.
Key Findings of the Study
Using ACTIMOT, the researchers activated 39 previously unknown natural products, including compounds from four entirely new chemical classes. These findings underscore the immense potential of this method to uncover previously hidden natural products.
Benefits of ACTIMOT:
Rapid Discovery: Speeds up the identification of novel bioactive compounds.
Broad Applicability: Can be applied across various bacterial species to mine their genomic potential.
Scalability: Enables large-scale production of promising compounds in alternative microbial hosts.
Implications for Drug Discovery
1. Combatting Antibiotic Resistance
The discovery of new antibiotics is critical in the fight against antibiotic-resistant bacteria. By unlocking hidden BGCs, ACTIMOT provides a powerful tool for identifying novel antimicrobial compounds.
2. Expanding the Therapeutic Pipeline
Beyond antibiotics, natural products are used in cancer treatments, immunosuppressants, and antiviral therapies. The ability to uncover new chemical classes opens the door to innovative treatments for a range of diseases.
3. Reducing Development Timelines
Traditional methods of activating BGCs can be slow and inefficient. ACTIMOT streamlines the process, significantly reducing the time from discovery to production.
Future Directions
The ACTIMOT technology marks a significant leap forward in natural product research, but its potential extends far beyond the current study. Future applications could include:
Expanding the method to more bacterial species.
Optimizing host strains for enhanced production efficiency.
Exploring synergies between multiple BGCs for combinatorial biosynthesis.
Conclusion
The CRISPR-Cas9-based ACTIMOT technology is a game-changer in the field of natural product discovery. By unlocking silent BGCs, it paves the way for the discovery of new therapeutic compounds that can address some of the most pressing challenges in medicine, including antibiotic resistance and cancer treatment.
This innovative approach highlights the untapped potential of bacterial genomes and sets the stage for a new era in drug discovery. With ACTIMOT, the future of natural product-based therapies is brighter than ever.
Reference
Autologous DNA mobilization and multiplication expedite natural products discovery from bacteria
About The Author
Darrell Drysen has over 25 years of experience in the Medical Device, Life Science, and Bio-Tech industries. As a technical leader, he holds patents in several fields including Brachytherapy, Electrophysiology, and Neurovascular implants. His outstanding ability to lead projects is evident from the numerous products he has taken from from concept through commercialization for both large companies and starts-ups. He joined ThermoGenesis in 2019 and is currently the Vice President of Operations.
Darrell holds certificates and degrees in Plastics Engineering Technology, Project Management, and Business Administration from California State University Sacramento and Cal Poly Pomona.
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