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

Tavia Caplan; Álvaro Lorente-Macías; Peter J Stogios; Elena Evdokimova; Sabrina Hyde; Melanie A Wellington; Sean Liston; Kali R Iyer; Emily Puumala; Tanvi Shekhar-Guturja; Nicole Robbins; Alexei Savchenko; Damian J Krysan; Luke Whitesell; William J Zuercher; Leah E Cowen

doi:10.1016/j.chembiol.2019.12.008

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

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

Tavia Caplan, Álvaro Lorente-Macías, Peter J Stogios, Elena Evdokimova, Sabrina Hyde, Melanie A Wellington, Sean Liston, Kali R Iyer, Emily Puumala, Tanvi Shekhar-Guturja, …

Cell chemical biology, Vol.27(3), pp.269-282.e5

03/19/2020

DOI: 10.1016/j.chembiol.2019.12.008

PMID: 31924499

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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-log10 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. [Display omitted] •Screen of kinase inhibitors identifies Yck2 kinase as a promising antifungal target•Clinical echinocandin resistance is reversed by pyrazolopyridine Yck2 inhibitors•Combination treatment eradicates fungus while sparing co-cultured human cells•Genetic depletion of YCK2 markedly impairs Candida albicans virulence in mice New agents are needed to counter infection by drug-resistant fungi. We screened protein kinase inhibitors for the ability to reverse antifungal resistance. Chemogenomic, biochemical, and structural data established Yck2 as the target of our most potent hit. Findings support inhibiting this kinase as a promising therapeutic strategy.

protein kinase inhibitor

casein kinase

pyrazolopyridine

fungal pathogen

caspofungin

Candida

Details

Title: Subtitle: Overcoming Fungal Echinocandin Resistance through Inhibition of the Non-essential Stress Kinase Yck2
Creators: Tavia Caplan - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Álvaro Lorente-Macías - Structural Genomics Consortium, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Peter J Stogios - Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5G 1M1, Canada
Elena Evdokimova - Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5G 1M1, Canada
Sabrina Hyde - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Melanie A Wellington - Departments of Pediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Sean Liston - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Kali R Iyer - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Emily Puumala - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Tanvi Shekhar-Guturja - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Nicole Robbins - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Alexei Savchenko - Center for Structural Genomics of Infectious Diseases (CSGID), Toronto, ON, M5G 1M1, Canada
Damian J Krysan - Departments of Pediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Luke Whitesell - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
William J Zuercher - Structural Genomics Consortium, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Leah E Cowen - Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada
Resource Type: Journal article
Publication Details: Cell chemical biology, Vol.27(3), pp.269-282.e5
DOI: 10.1016/j.chembiol.2019.12.008
PMID: 31924499
NLM abbreviation: Cell Chem Biol
ISSN: 2451-9456
eISSN: 2451-9448
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases; DOI: 10.13039/501100000024, name: Canadian Institutes of Health Research
Language: English
Date published: 03/19/2020
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984066346402771

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