The European Research Council (ERC) has awarded its prestigious €9.7 million  ($11.5 million) Synergy Grant jointly to researchers at Tel Aviv University (TAU) and Charité–Universitätsmedizin Berlin, according to a statement from the spokesperson’s department at TAU.

Research groups led by Professor Judith Berman, head of the Fungal Drug Response lab at TAU’s Shmunis School of Biomedical and Cancer Research, and Professor Markus Ralser, director of Charité’s Institute of Biochemistry, will now investigate the biological mechanisms that underlie the tolerance of fungal infections to antifungal drugs used to treat them. The goal is to inspire the development of new antifungal drugs and combination therapies that will be effective against lethal, invasive fungal infections

While most fungal infections are not life-threatening, up to half of all invasive fungal infections of the internal organs or bloodstream are fatal, and they are often difficult to treat. Some 1.6 million people die of invasive fungal infections every year, similar to the number of deaths from malaria or tuberculosis.

Currently, there are only three classes of drugs (azoles, echinocandins and polyenes) available to treat invasive fungal infections, in contrast to many more classes of antibacterial drugs. Because fungal and human (and other mammalian) cells are very similar, it is difficult to find medications that can inhibit the pathogen without causing unwanted side effects. Therefore, when resistance or tolerance to such existing drugs arises, it severely impacts the effective treatment of these fungal infections.

While the mechanisms of drug resistance have been studied extensively, mechanisms of drug tolerance—by which some fungal cells continue to grow slowly despite the presence of the drug—are only beginning to be understood. The teams led by Berman and Ralser will explore the role of transient metabolic responses in these fungal drug responses, which differ from classic bacterial drug-resistance mechanisms.

“The situation in fungal pathogens is fundamentally different from the situation with drug-resistant bacteria,” said Berman, according to the statement. “Resistance in fungal pathogens is not as common and does not spread as rapidly as bacterial resistance. Rather, we find that fungal pathogens rapidly give rise to a subset of cells that continue growing slowly when they encounter the antifungal drug. This property is transient, and cells can switch back and forth between the ‘tolerant’ and ‘non-tolerant’ state—it is not caused by the types of mutations that provide resistance as in bacterial infections. Rather, it is a ‘phenotypic process’ and we need to understand it in order to treat it most effectively.”

One of the key hypotheses behind anti-fungal tolerance is that it is caused by metabolism.

“We observed that cells of different types that grow together do so by exchanging metabolites and cooperating in metabolism,” added Ralser. “This metabolic cooperation makes cells heterogeneous. We also have evidence that metabolic heterogeneity might explain key aspects of drug tolerance mechanisms.”

The two researchers will now test thousands of fungal strains for antifungal tolerance and metabolic properties, and then compare them. The project will involve collaborations with clinicians and biologists across Europe, Canada and the United States.

The main goal of the work will be to discover the molecular processes responsible for fungal tolerance, and to exploit this knowledge to develop new therapeutic strategies and lead compounds that prevent pathogens from becoming drug-tolerant or drug-resistant.

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