Establishment of an innovative co-cultivation platform for high-throughput identification of antimicrobial compounds

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In the alarming context of the recurrent emergence of multi-resistant pathogenic bacteria and fungi, uncharted territories in microbiological research and bioprocess engineering must be explored. The prevailing method of growing pure (axenic) culture of microorganisms, as of today still the common praxis since its introduction by Robert Koch in the late XIX century, must be implemented with innovative technologies for the establishment of mixed-species cultures.The intensive investigation during the last two decades of genome sequence data from filamentous fungi and bacteria in the quest for new antibiotic and antimycotic genes led to the unexpected observation that in most sequenced species about 30-50 gene clusters are present, which similarly to penicillin from the fungus Penicillium chrysogenum could set in motion a new era in medicine. The surprise: most of the discovered gene clusters are inactive and do not lead to the production of a bioactive substance when bacteria and fungi are cultivated in axenic cultures. This potential cannot thus be fully exploited with methodologies used in classical microbiological studies and is one of the pivotal reasons why since about 20 years no new class of antibiotic could be identified from microbial pure cultures. The low-hanging fruits have been harvested and the end of the era of single-species cultivations muss be ushered. Scientific breakthroughs can be achieved by considering the metabolic activities of mixed-species cultures including the analysis of the metabolism of yetuncultivable microorganisms that are not viable as pure cultures. This analysis must occur at the systems biology level (transcriptomic, proteomic and metabolomics) to allow for a holistic, from genotype-to-chemotype understanding of microbial metabolism as well as to provide new technical approaches for a controlled and reproducible cultivation methodology to ensure the generation of reliable and robust data.The research concept of the present proposal meets the requirements for the development of new co-cultivation approaches and methodologies for the stable in vitro cultivation of natural, complex mixed-species populations of microorganisms for the discovery of hitherto unknown substances and substance classes for current societal and medical challenges, their bioactivity testing as antibacterials and antifungals as well as the correlation with the corresponding genetic clusters.