Project description
Shedding light on the mechanisms of antifungal drug tolerance
Despite the use of antifungal drugs, invasive fungal infections can lead to mortality in nearly 50 % of cases. Treatment failure may be a result of drug tolerance, which, is incompletely understood. The scope of the EU-funded FungalTolerance project is to reach a fundamental understanding of this type of tolerance. Researchers will carry out genomic and proteomic analysis of more than 1 000 fungal isolates and identify the biological mechanisms that drive drug tolerance in them. Moreover, they will screen candidate compounds that suppress tolerance and pave the way for novel, more effective antifungal strategies.
Objective
Mortality from invasive fungal infections approaches 50%, despite the use of available antifungal drugs. While bacterial studies have focused on drug resistance, the rare appearance of antifungal drug resistance does not explain these treatment failures. Antifungal tolerance is a poorly understood property that is expressed to different degrees in different non-resistant isolates, yet has not been measured routinely in the clinic or in most research studies. We do not know how tolerance differs between isolates, what biological mechanisms drive it, how it affects only some cells in a single isolate, or whether it can be inhibited to improve treatment outcomes. Recently, the Berman lab found that tolerance is an intrinsic property, in which some cells of a non-resistant isolate continue growing in the presence of the drug that has the potential to explain antifungal treatment failures. In parallel, the Ralser lab found that inhibitors of metabolic pathways affect the stress survival of some cells and the Berman lab found that these inhibitors can clear tolerance and convert an antifungal drug from fungistatic to fungicidal, thereby killing the cells and halting their adaptation. Together, we combine expertise in pathogenic fungi (Berman) and metabolic systems (Ralser) to reach fundamental understandings of tolerance across the range of its biological scales by: 1) capturing the diversity of tolerance in a genomic and proteomic data resource of >1000 isolates; 2) identifying metabolic pathways and molecular mechanisms that drive tolerance within isolates; and 3) probing processes and compounds that affect phenotypic heterogeneity between cells and suppress tolerance. By elucidating the mechanisms that drive tolerance and fungal single-cell diversity, we propose to render tolerance targetable, providing a paradigm shift in anti-fungal treatment strategies.
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Funding Scheme
ERC-SyG - Synergy grantHost institution
69978 Tel Aviv
Israel