Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging

Norman Rhijn, Can Zhao, Narjes Al-Furaiji, Isabelle S. R. Storer, Clara Valero, Sara Gago, Harry Chown, Clara Baldin, Rachael-Fortune Grant, Hajer Shuraym, Lia Ivanova, Olaf Kniemeyer, Thomas Krüger, Elaine Bignell, Gustavo H. Goldman, Jorge Amich, Daniela Delneri, Paul Bowyer, Axel A. Brakhage, Hubertus Haas and Michael J. Bromley ()
Additional contact information
Norman Rhijn: Faculty of Biology, Medicine and Health, University of Manchester
Can Zhao: Faculty of Biology, Medicine and Health, University of Manchester
Narjes Al-Furaiji: Faculty of Biology, Medicine and Health, University of Manchester
Isabelle S. R. Storer: Faculty of Biology, Medicine and Health, University of Manchester
Clara Valero: Faculty of Biology, Medicine and Health, University of Manchester
Sara Gago: Faculty of Biology, Medicine and Health, University of Manchester
Harry Chown: Faculty of Biology, Medicine and Health, University of Manchester
Clara Baldin: Biocenter, Innsbruck Medical University
Rachael-Fortune Grant: Faculty of Biology, Medicine and Health, University of Manchester
Hajer Shuraym: Faculty of Biology, Medicine and Health, University of Manchester
Lia Ivanova: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Olaf Kniemeyer: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Thomas Krüger: Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI)
Elaine Bignell: Faculty of Biology, Medicine and Health, University of Manchester
Gustavo H. Goldman: Universidade de São Paulo, Ribeirão Preto
Jorge Amich: Faculty of Biology, Medicine and Health, University of Manchester
Daniela Delneri: Faculty of Biology, Medicine and Health, University of Manchester
Paul Bowyer: Faculty of Biology, Medicine and Health, University of Manchester
Axel A. Brakhage: Institute of Microbiology, Friedrich Schiller University
Hubertus Haas: Biocenter, Innsbruck Medical University
Michael J. Bromley: Faculty of Biology, Medicine and Health, University of Manchester

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.

Date: 2024
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DOI: 10.1038/s41467-024-48592-8

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