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Unraveling the complexity of fungal drug tolerance at multiple scales of biology

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.

Field of science

  • /medical and health sciences/basic medicine/pharmacology and pharmacy/drug resistance

Call for proposal

ERC-2020-SyG
See other projects for this call

Funding Scheme

ERC-SyG - Synergy grant

Host institution

TEL AVIV UNIVERSITY
Address
Ramat Aviv
69978 Tel Aviv
Israel
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 4 281 250

Beneficiaries (3)

TEL AVIV UNIVERSITY
Israel
EU contribution
€ 4 281 250
Address
Ramat Aviv
69978 Tel Aviv
Activity type
Higher or Secondary Education Establishments
CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany
EU contribution
€ 4 989 668
Address
Chariteplatz 1
10117 Berlin
Activity type
Higher or Secondary Education Establishments
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France
EU contribution
€ 420 000
Address
Rue Michel Ange 3
75794 Paris
Activity type
Research Organisations