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Source: Charite – Universitatsmedizin Berlin Systematic causal research at Charité and Tel Aviv University Biochemistry and systems biology of metabolism – focus of the laboratory Prof. Ralser. Photo: Janie Airey. Joint press release of the Charité and the University of Tel Aviv Working groups at the Charité – Universitätsmedizin Berlin and the University of Tel Aviv will investigate how invasive fungal pathogens escape treatment and develop tolerance to antifungal substances over the next six years can. Basic knowledge of pathogenic fungi on the one hand and discoveries on the level of cell metabolism on the other hand come together in this jointly managed project. A Synergy Grant from the European Research Council (ERC) supports the extensive project with a total of 9.7 million euros. Fungal infections are widespread and in many cases not life-threatening. An exception, however, are invasive fungal infections, which can contribute to sepsis – a serious, systematic reaction of the organism to an uncontrolled infection. Fungal diseases of this type have a mortality rate of up to 50 percent, are usually difficult to treat, and are associated with at least 1.6 million deaths annually. In contrast to bacterial infections, for which several antimicrobial drugs are available, only three special classes of active substances have so far proven to be clinically effective against invasive fungal infections. The fact that so few effective drugs are available is partly due to the similarity of the cells of humans and mammals and of fungal cells. Accordingly, there are only a few fungal-specific targets for drugs. In addition, not only very few anti-fungal drugs are available, the effectiveness of these preparations also decreases. For example, about half of the invasive infections caused by Candida albicans, the so-called thrush fungus and most common human pathogens, cannot be effectively controlled by fluconazole, the most common antifungal agent in this situation. Therapy failures like this can be partly explained by a tolerance or resistance of the fungal pathogens to anti-fungal drugs. This allows fungal cells to continue to grow despite treatment. What exactly causes the treatment of fungal diseases to fail is what the teams headed by Prof. Dr. Markus Ralser, Director of the Institute for Biochemistry and Head of the Biochemistry and Systems Biology of Metabolism Group at the Charité, and Prof. Dr. Judith Berman, research group leader at the Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences at Tel Aviv University. One of the central hypotheses here: The cause may be found in the metabolic process. “We have already observed in studies that different cell types work together by exchanging metabolites, such as nutrients, and thereby jointly develop a tolerance,” explains Prof. Ralser. “This metabolic cooperation leads to an alignment of the cells. We have indications that this metabolism-based heterogeneity could be a key for processes such as drug resistance or tolerance. Inhibitors of metabolic pathways also seem to influence the stress survival of some cells. ”The research teams in Berlin and Tel Aviv will now examine the underlying biological mechanisms in detail. “The situation with invasive fungal pathogens differs fundamentally from the situation with antibiotic-resistant bacteria”, as Prof. Berman describes. “In problematic bacterial infections, pathogens often acquire mutations that make them resistant to antibiotics. However, resistance to disease-causing fungi is not as common and does not spread as quickly. Here we find that fungal cells become heterogeneous and adapt to their environment, with some of the cells continuing to grow slowly even under the influence of an anti-fungal drug. Examining these growing cells shows that drug-resistant and non-resistant cells grow in a similar way to the original fungal strains. Resilience or resistance is therefore inherent in the cells themselves and is not caused by similar types of mutations as is the case with bacterial infections. ”In a highly interactive work program, Prof. Berman and Prof. Ralser will now test thousands of fungal strains Test drug resistance and compare their properties at the metabolic level. To this end, they will work with clinicians and biologists across Europe, Canada, and the United States. The common goal is to decipher the molecular pathways that explain drug resistance in fungal diseases. In addition, they want to develop new concepts and lead substances that prevent pathogenic fungal cells from increasing tolerance or resilience to drugs. The scientists want to contribute to the development of new antimycotics and combination therapies that are effective against deadly invasive fungal infections.

Prof. Dr. Markus Ralser studied genetics and molecular biology in Salzburg, Austria and completed his PhD in the field of neurodegenerative diseases at the Max Planck Institute (MPI) for molecular genetics in Berlin. After receiving training in mass spectrometry at VU Amsterdam, the Netherlands, he founded a junior group at the MPI for Molecular Genetics in Berlin. He then moved this to the University of Cambridge in Great Britain in 2011. Since 2013 he has been a group leader at the Francis Crick Institute in London. In 2018 he received the Einstein Professorship for Biochemistry and has since been one of two heads of the Department of Biochemistry at the Charité. His work focuses on the central carbohydrate and amino acid metabolism, for example the evolutionary origin of the carbohydrate metabolism, the metabolic response to oxidative stress, or the application of self-establishing yeast communities to investigate nutrient exchange. His work has received several awards, including the EMBO Gold Medal, the BioMed Central Research Award, the Starling Medal and the Colworth Medal. Dr. Judith Berman received her PhD from the Faculty of Biology at the Weizmann Institute of Science in Israel and began her work as an Associate Professor at the University of Minnesota. A little later she was able to accept a professorship at McKnight University, Department of Genetics & Cellular Biology. In 2012 she took over a professorship in the Department of Molecular Cell Biology at Tel Aviv University, Israel. Prof. Berman is a leading global expert in the field of research into tolerances in fungal pathogens and has received numerous awards and honors. This includes membership in the European Molecular Biology Organization and the Genetics Society of America, she is also a Fellow of the American Academy for the Advancement of Science and a Fellow of the American Academy of Microbiology (ASM). ERC Synergy Grant: The European Research Council supports Synergy Grants teams of two to four excellent scientists. The projects should lead to discoveries at the interfaces between disciplines and to substantial advances at the borders of knowledge. The prerequisite is that the project is only possible through cooperation between the researchers. The maximum funding amount per project is ten million euros for a period of up to six years.

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LinksDepartment of Biochemistry at the CharitéPress release of the European Research Council

ContactProf. Dr. Markus RalserDirector of the Institute for Biochemistry Charité – Universitätsmedizin Berlint: +49 30 450 528 142

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