Cited by 57Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2

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Caplan, Tavia, Lorente-Macías, Álvaro, Stogios, Peter J., Evdokimova, Elena, Hyde, Sabrina, Wellington, Melanie A., Liston, Sean, Iyer, Kali R. +8 more·2020·Cell Chemical Biology

Abstract

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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Crossref · 10.1016/j.chembiol.2019.12.008

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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.
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
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
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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