Nature offers a virtually limitless variety of chemical substances. Although these have been optimized over millions of years of evolution for their respective purposes, they have not been optimized for use as active ingredients in humans. For decades, researchers have therefore been attempting to genetically reprogram microbial producers of active ingredients so that they produce variants of their natural compounds with improved pharmaceutical properties. A major challenge in this endeavor is that the protein structures responsible for the production of natural products are extremely complex. Many changes to the corresponding blueprints therefore simply result in non-functional proteins. A team led by HIPS Junior Research Group Leader Dr. Kenan Bozhüyük has now addressed this problem with a new approach based on artificial intelligence. The idea is that if an AI can understand what makes production systems work, it may even be able to develop new building blocks for such systems that do not occur in nature—thereby further expanding chemical diversity for drug discovery. HIPS is a site of the Helmholtz Centre for Infection Research in collaboration with Saarland University.
The study focused on so-called non-ribosomal peptide synthetases, or NRPS for short. These large enzyme complexes function like molecular assembly lines. They produce a wide variety of biologically active natural compounds in microorganisms, including substances that have served as the basis for the development of numerous antibiotics, immunosuppressants, and cancer drugs. The problem is that a product can only be formed if the individual components interact precisely at the right moment. This is why NRPS are particularly difficult to modify in a targeted manner.
The researchers combined several pre-trained AI models with experimental test series to develop new so-called thiolation domains (T-domains). These building blocks act like movable transport arms within the NRPS: they pick up molecular intermediates and pass them on to the next processing station. In total, the team used AI to design 76 new T-domains, produced hundreds of different NRPS variants, and tested them in living cells.
The results showed that several of the AI-designed building blocks were functional. Some even enabled the formation of products in artificially combined enzyme systems and increased the yield up to three times compared to natural variants. In addition, at least one of the designed proteins proved to be more soluble and thermally more stable than the natural counterpart. Higher yields are not only important for future production. They also make it easier, even in the early stages of research, to obtain new natural compounds in sufficient quantities to determine their structure and investigate their effects more closely. A key factor was that the AI did not design the new building blocks in isolation, but rather tailored them to their immediate surroundings within the respective enzyme system. This is because whether such a building block functions depends heavily on its ability to interact with its neighboring regions.
“Our results show that artificial intelligence can be used not only to design individual proteins, but also to specifically redesign key building blocks of complex biological production systems,” says Bozhüyük. “AI does not replace experiments, but it helps us select promising candidates more quickly from among many possible variants.”
“The study shows that AI can significantly advance the development of new active compounds based on natural products,” says Prof. Rolf Müller, Scientific Director of HIPS and head of the department “Microbial Natural Products”. “If we can adapt such biosynthetic systems in a more targeted manner in the future, this will open up new possibilities for developing urgently needed drugs more efficiently and thus making them available for clinical applications more quickly.”
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defense mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. https://www.helmholtz-hzi.de/en
Helmholtz Institute for Pharmaceutical Research Saarland:
The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken is a branch of the Helmholtz Centre for Infection Research (HZI) in Braunschweig and was established by the HZI and Saarland University in 2009. Its researchers are searching mainly for new agents against infectious diseases, optimise these agents for application in humans and research ways how these agents can be transported best through the body to the site of action. https://www.helmholtz-hips.de/en/
Nature Communications
Experimental study
Cells
Generative AI designs functional thiolation domains for reprogramming non-ribosomal peptide synthetases
22-Sep-2026