Identification and Characterization of Fungal RiPPs

On a quest to uncover new medicinal compounds in fungi Vienna, Austria. A young research team at TU Wien rises to the challenge of discovering and investigating a yet understudied group of substances in fungi. These so called RiPPs are different compounds with a variety of effects. Some of them are harmful, for instance the toxin of the fungus death cap, while some RiPPs are highly beneficial and have antibacterial properties. Within the research project, new RiPPs shall be discovered and described, laying the foundation for the development of new pharmaceuticals. Extracts from fungi have a long tradition as natural and effective medicines. The best known example is probably penicillin. These substances can be divided into different groups according to their basic chemical structure. A yet understudied group of these substances in fungi are the so-called RiPPs (ribosomally synthesized and post-translationally modified peptides). RiPPs are peptides, this means linked amino acids that are modified in the cells of the fungi in order to improve stability and effectiveness. Fungi naturally produce these RiPPs for different reasons. For instance, toxins to protect themselves from predators or antibiotics to compete against other fungi and bacteria. Especially, these antibacterial effects make RiPPs an interesting and promising research target. A bioinformatician, a molecular biologist and a chemical analyst are working closely together in the newly started project. First, genes that could be responsible for RiPPs are searched for in various fungi. The gene can be activated by targeted molecular biology manipulation allowing the investigation and analysis of new RiPPs. The team aspires not only to discover new RiPPs but also to develop new molecular biological and analytical methods that can benefit other research groups reasearching RiPPs. Contact: Christian Derntl, christian.derntl@tuwien.ac.at

Fungal secondary metabolism is a vast and largely untapped resource for discovering new compounds with a wide range of bioactive properties. These secondary metabolites can be grouped into different classes based on their chemical structures. One relatively understudied class is known as RiPPs (ribosomally synthesized and post-translationally modified peptides). These are short peptides that often undergo extensive chemical modifications, resulting in unique and potentially useful compounds. Prior to this project, we developed a novel tool for predicting RiPPs through genome mining. In this project, our goal was to activate the genes responsible for RiPP production and identify any new compounds they might produce. This was a high-risk endeavor with an uncertain outcome. In this case, the risk did not pay off as we were unable to discover any new RiPPs. To build on the project, we broadened our approach and activated genes involved in the production of other types of secondary metabolites in the fungus Trichoderma reesei. This led to an exciting breakthrough: the discovery of a completely new compound, ilicicolin K-a polyketide with strong antifungal properties. Ilicicolin K has potential applications in both medicine and agriculture. In addition, we found that several previously known compounds all originate from a single biosynthetic gene cluster (BGC), which allowed us to link their biosynthetic pathways into a larger, interconnected biosynthetic network.