Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2
Open accessAbstract
New strategies are urgently needed to counter the threat to human health posed by drug-resistant fungi. To explore an as-yet unexploited target space for antifungals, we screened a library of protein kinase inhibitors for the ability to reverse resistance of the most common human fungal pathogen, Candida albicans, to caspofungin, a widely used antifungal. This screen identified multiple 2,3-aryl-pyrazolopyridine scaffold compounds capable of restoring caspofungin sensitivity. Using chemical genomic, biochemical, and structural approaches, we established the target for our most potent compound as Yck2, a casein kinase 1 family member. Combination of this compound with caspofungin eradicated drug-resistant C. albicans infection while sparing co-cultured human cells. In mice, genetic depletion of YCK2 caused an ∼3-log 10 decline in fungal burden in a model of systemic caspofungin-resistant C. albicans infection. Structural insights and our tool compound's profile in culture support targeting the Yck2 kinase function as a broadly active antifungal strategy.
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CK1 family members Yck2 and Hrr25 are implicated in FKS1-mediated echinocandin resistance in C. albicans.
“More recently, the casein kinase 1 (CK1) family members, Yck2 and Hrr25, were implicated in FKS1-mediated echinocandin resistance in C. albicans88,89.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [88]
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- Authors
- Caplan, T., Lorente-Macías, Á., Stogios, P. J., Evdokimova, E., Hyde, S., Wellington, M. A., Liston, S., Iyer, K. R., Puumala, E., Shekhar-Guturja, T., Robbins, N., Savchenko, A., Krysan, D. J., Whitesell, L., Zuercher, W. J., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- University of Iowa (US)
- University of Calgary (CA)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Cowen, Leah E.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 27
- Issue
- 3
- Pages
- 269-282.e5
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC7093242
- OpenAlex
- W2999244147
- Cited by
- 57
- References
- 78
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 12 · 2023: 10 · 2022: 9 · 2021: 8 · 2020: 7
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Pfizer
- Wellcome Trust (106169/ZZ14/Z)
- Merck
- Takeda Canada
- Biological and Environmental Research (DE-AC02-06CH11357)
- Canadian Institutes of Health Research (FDN-154288)
- Argonne National Laboratory
- Innovative Medicines Initiative
- Janssen Pharmaceuticals
- National Institute of Allergy and Infectious Diseases
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill
- Boehringer Ingelheim
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- Genome Canada
- Ministerio de Educación, Cultura y Deporte (1097737, 14/00818)
- U.S. Department of Energy
- Novartis Pharma
- U.S. Department of Health and Human Services (HHSN272201700060C)
- Ontario Ministry of Economic Development and Innovation
- Meso Scale Diagnostics
- Canada Foundation for Innovation
- Canadian Institute for Advanced Research
- Canada Research Chairs
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- echinocandin resistance, caspofungin resistance, Candida albicans, casein kinase 1, protein kinase inhibitors, antifungal drug targets, combination antifungal therapy, systemic fungal infection, chemical genomics
- MeSH terms
- Animals, Antifungal Agents, Candida albicans, Candidiasis, Cells, Cultured, Fungal Proteins, Humans, Microbial Sensitivity Tests, Molecular Structure, Drug Resistance, Fungal, Protein Kinase Inhibitors, Mice, Echinocandins
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