The goal of the research is to lead to the development of antifungal drugs and combined treatments that will be effective against life-threatening invasive fungal infections
The European Research Council, the research body of the European Commission, awarded one of the most significant research grants for collaborative studies, the Synergy Grant, for a total of 9.7 million Euros to Tel Aviv University and the Charita University of Medicine Berlin.
The research groups are led by Prof. Judith Berman, Head of the Antifungal Drug Development Laboratory at the Shemunis School of Biomedical and Cancer Research, George Weiss Faculty of Life Sciences, Tel Aviv University, and Prof. Marcus Resler, Director of the Institute of Biochemistry At Sharita University and the head of the research group 'Biochemistry and Biology of Metabolic Mechanisms', will begin to investigate the biological mechanisms that enable tolerance of fungal pathogens. The purpose of the research is to lead to the development of antifungal drugs and combined treatments that will be effective against life-threatening invasive fungal infections.
Most fungal infections, such as skin infections, oral and vaginal infections, are not life-threatening. The notable exceptions are invasive fungal infections of internal organs or the bloodstream. They are difficult to treat, have a high mortality rate (which can reach up to 50%) and kill about 1.6 million people every year, similar to malaria and tuberculosis. There are only 3 types of drugs that have been shown to be effective against invasive fungal infections (azole drugs, echinocandins, and polyenes), compared to bacterial infections that can be treated by many antimicrobial drugs. The lack of effective drugs is due to the similarity between fungal cells and human cells (as well as other mammals) which creates difficulty in finding suitable drugs that will not cause side effects in patients. The development of resistance or tolerance to such drugs significantly limits the ability of doctors to treat these types of fungal infections. While the mechanisms of resistance have been extensively studied, the mechanisms of drug tolerance, in which some fungal cells continue to grow at a slow rate despite the presence of the drug, are more complex and we are only at the beginning of understanding them. The Synergistic Research Grant to study the development of fungal tolerance will focus on studying the role of metabolic responses in the overall response of fungi to drugs. These mechanisms are different from the classic mechanisms of bacterial drug resistance.
Drug resistance that is not due to genetic reasons as in bacteria
"Fungal infections are essentially different from resistant bacterial infections," explains Prof. Berman. "In a problematic bacterial infection, the pathogen accumulates mutations that make it resistant to antibiotics. In contrast, resistance to fungal pathogens is not as common and does not spread as quickly. We found that pathogenic fungal cells rapidly produce a set of cells that continue to grow at a slower rate after the encounter with the antifungal drug. This feature is transient and the cells can switch between a state of "tolerant" and "intolerant". Therefore, the resistance is phenotypic and does not arise as a result of similar mutations leading to resistance, as it happens in a bacterial infection."
The main hypothesis that the tolerance to the antifungal drugs is caused by metabolic mechanisms. "We observed cells from different strains growing together. They do this by exchanging metabolites and metabolic cooperation," adds Prof. Resler. "The metabolic cooperation causes the cells to be heterogeneous. We also saw evidence that metabolic heterogeneity can explain key points in the tolerance mechanism."
In their interactive work program, Prof. Berman and Prof. Resler will test the tolerance of thousands of pathogenic and environmental fungal strains and compare their metabolic properties. To this end, they will collaborate with clinical doctors and biologists throughout Europe, Canada, and the USA. Their goal is to find molecular pathways that will explain the fungal tolerance and thus pave the way for the development of therapeutic strategies and new compounds to prevent the development of tolerance against the drugs.
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