Microorganisms generate a diverse range of natural substances that can serve as active components in the treatment of illnesses like infections or cancer. The genetic instructions for creating these compounds are stored within the microbes’ DNA, yet they frequently remain inactive in laboratory settings. Recently, a group of researchers has pioneered an innovative genetic technique, utilizing a natural mechanism found in bacteria for genetic transfer to create new active compounds.
Microorganisms generate a diverse range of natural substances that can serve as active components in the treatment of illnesses like infections or cancer. The genetic instructions for creating these compounds are stored within the microbes’ DNA, yet they frequently remain inactive in laboratory settings. A group of researchers at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) has pioneered an innovative genetic technique, utilizing a natural mechanism found in bacteria for genetic transfer to create new active compounds. The findings were published in the journal Science.
Bacteria possess a unique capability to exchange genetic material among themselves, unlike humans. A significant instance of this is the transmission of antibiotic resistance genes amongst bacterial pathogens, which facilitates rapid adaptation to various environments and contributes to the growing problem of antibiotic resistance. Researchers at HIPS and the German Center for Infection Research (DZIF) have tapped into this natural process to extract and amplify genetic blueprints for new bioactive compounds from bacteria, referred to as biosynthetic gene clusters. Their novel strategy, named “ACTIMOT,” allows for either the direct production of the natural substances encoded in these gene clusters within the original bacterium or their transfer to more suitable microbial strains for molecule creation. HIPS operates in coordination with the Helmholtz Centre for Infection Research (HZI) and Saarland University.
ACTIMOT—short for “Advanced Cas9-mediaTed In vivo MObilization and mulTiplication of BGCs”—utilizes CRISPR-Cas9 technology, often dubbed “gene scissors,” enabling precise modifications within bacterial DNA. Since biosynthetic gene clusters typically show lower activity in labs, ACTIMOT extracts them from the genome and inserts them into a mobile genetic unit, which the bacterium can then replicate. This series of actions takes advantage of the same molecular mechanisms that allow bacteria to share resistance genes amongst themselves. In many cases, amplifying these gene clusters on what’s known as plasmids is already sufficient for producing the encoded natural products. If needed, the generated plasmids can easily be transferred to a different production strain to facilitate the synthesis of the natural substances. The researchers report successful outcomes for both methods in their study.
“Numerous biosynthetic gene clusters remain inactive under lab conditions for various reasons, and existing methods to uncover the natural products they encode only target a limited few,” states Chengzhang Fu, junior research group leader at HIPS and the study’s last author. “Our method replicates the natural bacterial gene transfer process, enabling us to directly extract and amplify entire biosynthetic gene clusters within the native bacterial organism, exposing us to previously hidden natural products. This technology allows us to explore the biosynthetic capabilities of bacteria more swiftly and efficiently compared to current methods.”
The team has already proven that ACTIMOT can lead to new findings: In their study, they identified 39 new natural products from four previously unrecognized classes of natural substances. These breakthroughs bolster the team’s belief that ACTIMOT could significantly speed up the discovery of new drug candidates. “Microorganisms present us with immense potential for generating new chemical entities that we can utilize to develop urgently required active ingredients,” explains Rolf Müller, head of department and scientific director of HIPS, who also coordinated the ‘New Antibiotics’ research area at DZIF and played a key role in the study. “To date, many aspects of this microbial bounty have remained concealed. ACTIMOT will enable us to better harness the biosynthetic capabilities of bacteria, greatly enhancing the advancement of new active agents.”
In the current research, ACTIMOT has been applied to bacteria of the genus Streptomyces. However, the authors plan to expand its applicability to other bacterial species known for their potential to produce unexplored natural products. Additionally, ACTIMOT shows promise for use in various other fields, including the mass production of valuable natural substances, uncovering new gene pathways, and discovering opportunities for optimizing natural products.