Reviewed by Emily Henderson, B.Sc.Nov 10 2020

Over the next six years, research groups at Charit - Universittsmedizin Berlin and Tel Aviv University will study how invasive fungal pathogens are able to evade treatments and develop tolerance to antifungal drugs. In addition to generating fundamental knowledge of fungal pathogens, this large project aims to provide new insights into fungal cell metabolism. This joint endeavor is supported by a European Research Council ERC Synergy Grant worth approximately 9.7 million.

While fungal infections are extremely common, they are not usually life-threatening. Invasive fungal infections, however, are an exception, as they can lead to sepsis, a severe condition caused by an extreme systemic response to uncontrolled infection. Fungal infections of this kind can have a mortality of up to 50 percent, are often difficult to treat, and are responsible for at least 1.6 million deaths per year.

While bacterial infections can be treated with a range of antimicrobial drugs, only three classes of drugs (azoles, echinocandins and polyenes) have been shown to be effective against invasive fungal infections. Reasons for the paucity of effective drugs include the fact that fungal and human (and other mammalian) cells are very similar, which leaves very few pathogen-specific drug targets to choose from.

In addition to the dearth of antifungals, the situation is further exacerbated by the declining efficacy of these drugs. For instance, the drug of choice in the treatment of invasive candidiasis, fluconazole, is ineffective in approximately half of all invasive infections caused by Candida albicans, the most common human pathogen (better known as the organism responsible for thrush). Treatment failures such as these are, in part, explained by pathogen tolerance, a phenomenon which allows fungal cells to continue growing in the presence of an antifungal drug.

Under the leadership of Prof. Dr. Markus Ralser (Director of Charit's Institute of Biochemistry and Group Leader of the 'Biochemistry and Metabolic Systems Biology' research group) and Prof. Dr. Judith Berman (head of the Judith Berman Lab at Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University) a leading expert in fungal pathogens, the research teams are hoping to identify the precise mechanisms responsible for these treatment failures. One of their key hypotheses is that the explanation may be found in metabolic processes.

Our previous observations revealed that different types of cells work together. This collaboration involves the exchange of metabolites such as nutrients and results in the cells jointly developing tolerance. This metabolic collaboration makes cells heterogeneous. We have evidence that this metabolic heterogeneity may be a key factor in drug tolerance. Furthermore, inhibitors of metabolic pathways appear to influence the stress survival mechanisms in some of these cells."

Prof. Dr. Markus Ralser, Director of Charit's Institute of Biochemistry and Group Leader of the 'Biochemistry and Metabolic Systems Biology' research group

Both the Berlin and Tel Aviv research teams will now study the underlying biological mechanisms in great detail. "The situation regarding invasive fungal pathogens is fundamentally different from that involving antibiotic-resistant bacteria," explains Prof. Berman. She adds: "In problematic bacterial infections, pathogens often acquire mutations which render them resistant to antibiotics. In fungal pathogens, however, resistance is far less common and spreads less rapidly. Rather, what we find is that fungal cells become heterogeneous and adapt to their immediate environment. A proportion of cells continue to grow slowly, even in the presence of an antifungal drug. An examination of these growing cells shows that the growth exhibited by both drug-tolerant and non-tolerant cells is similar to that of the original strains. Cellular tolerance is therefore a phenotypic trait; it is not caused by mutations akin to those seen in bacterial resistance."

Their highly interactive work program will see Prof. Berman and Prof. Ralser work together to test thousands of fungal strains, establishing their drug tolerance levels and comparing their metabolic characteristics. To do so, they will work with clinicians and biologists from across Europe, Canada and the United States. Their common aim is to identify the molecular pathways which explain drug tolerance in fungal pathogens. The researchers also hope to develop new concepts and drugs which will be effective in preventing fungal pathogens from developing increased tolerance to antifungal drugs. The researchers are hopeful that their work will contribute to the development of new antifungal agents and new combination antifungal therapies which will be effective against life-threatening invasive fungal infections.

Prof. Markus Ralser studied genetics and molecular biology at the University of Salzburg and completed a PhD in neurodegenerative disorders at the Max Planck Institute (MPI) for Molecular Genetics in Berlin. Following his training in mass spectrometry at VU Amsterdam (Netherlands), he set up a Junior Research Group at the MPI for Molecular Genetics in Berlin, which he eventually moved to the University of Cambridge (United Kingdom) in 2011. He has been a Group Leader at the Francis Crick Institute in London since 2013. Markus Ralser became Einstein Professor of Biochemistry in 2018 and is one of the two Directors of Charit's Department of Biochemistry. His work focuses on central carbon metabolism (including the evolutionary origins of central carbon metabolism), amino acid metabolism, the metabolic responses to oxidative stress, and the use of self-establishing communities to study the exchange of metabolites in yeast. Prof. Ralser's numerous awards include the EMBO Gold Medal, the BioMed Central Research Award, the Starling Medal and the Colworth Medal.

Prof. Judith Berman completed her PhD at the Faculty of Biology, Weizmann Institute of Science (Israel). After starting her lab as Associate Professor at the University of Minnesota, her steep career path quickly led to her becoming a Distinguished McKnight University Professor at the Department of Genetics & Cellular Biology. In 2012, she became a Full Professor at the Department of Molecular Cell Biology, Tel Aviv University (Israel). Prof. Berman is a world-leading expert in fungal pathogen tolerance and holds numerous awards and honors. She is a researcher at the Shmunis School of Biomedical and Cancer Research at Tel Aviv University, and in addition to being a Member of the EMBO 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).

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ERC Synergy project explores causes of drug tolerance in intractable fungal infections - News-Medical.net