Epi- and chemogenomic engineering to find novel Natural Bioactive molecules from Fungi

Agricultural plant production needs pathogen and pest control, even more so as climate change imposes additional risks through weakening natural defense system of plants and the introduction of novel pathogens into temperate production areas. Moreover, development of pathogen or pest populations that are resistant against commonly used pesticides and toxic effects against non-target organisms and the environment poses additional risks. Especially the use of molecules with the same mode-of-action in medicine and agriculture fosters the spread of cross-resistances. Therefore, novel natural bioactive compounds are needed that should be highly effective and specific to the pathogen or pest target, optimally have more than one mode-of action and at the same time being almost not toxic to other organisms and environment. Traditional searches to find such novel molecules often used microbial sources as these organisms produce a wealth of natural bioactive substances for their own defense or communication. However, over the last decades, few new substances were identified, although genomic analyses of the microbes predicted a much higher chemical diversity than so far retrieved from them. Data originating from our laboratory for the first provided a mechanistic, chromatin-based molecular-genetic explanation for this undiscovered chemical richness. In combination with large-scale genome sequencing of fungi and oomycetes these discoveries provide new technical means for successful genome mining campaigns in fungi that allow a much better exploration of the high chemical diversity of fungi. In this translational science project we propose to use this basic knowledge for the revelation of novel natural bioactive substances from the hidden chemical space of fungi. From previous small-scale screenings and additional preliminary data we have generated already solid proof-of-concept that many novel molecules can be found using this strategy. We propose here to systematically employ chromatin-modifying methods and exploit our large and diverse in-house strain collection in a high-throughput (HTP) screening format. The techniques and infrastructure for this endeavor are available at our institute and the associated BMOSA core-facility (https://boku.ac.at/cf/bmosa).