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

van Rhijn, N ORCID: https://orcid.org/0000-0001-6722-2757, Zhao, C ORCID: https://orcid.org/0000-0002-0508-0236, Al-Furaji, N ORCID: https://orcid.org/0000-0001-5338-6443, Storer, ISR, Valero, C, Gago, S ORCID: https://orcid.org/0000-0002-7027-4598, Chown, H ORCID: https://orcid.org/0000-0002-5331-4711, Baldin, C ORCID: https://orcid.org/0000-0002-3895-9511, Grant, RF, Bin Shuraym, H ORCID: https://orcid.org/0009-0004-3256-0827, Ivanova, L, Kniemeyer, O ORCID: https://orcid.org/0000-0002-9493-6402, Krüger, T, Bignell, E ORCID: https://orcid.org/0000-0001-7748-1920, Goldman, GH ORCID: https://orcid.org/0000-0002-2986-350X, Amich, J ORCID: https://orcid.org/0000-0002-8987-5115, Delneri, D ORCID: https://orcid.org/0000-0001-8070-411X, Bowyer, P ORCID: https://orcid.org/0000-0002-1083-9286, Brakhage, AA, Haas, H ORCID: https://orcid.org/0000-0003-2472-9878 and Bromley, MJ ORCID: https://orcid.org/0000-0002-7611-0201 (2024) Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging. Nature Communications, 15 (1). 4984. ISSN 2041-1723

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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.