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Cited by 30Fungal and yeast genetics researchAntifungal resistance and susceptibilityFungal Infections and Studies

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

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van Rhijn, Norman, Zhao, Can, Al-Furaiji, Narjes, Storer, Isabelle S. R., Valero, Clara, Gago, Sara, Chown, Harry, Baldin, Clara, Grant, Rachael-Fortune, Bin Shuraym, Hajer, Ivanova, Lia, Kniemeyer, Olaf, Krüger, Thomas, Bignell, Elaine, Goldman, Gustavo H., Amich, Jorge, Delneri, Daniela, Bowyer, Paul, Brakhage, Axel A., Haas, Hubertus, Bromley, Michael J.·2024·Nature Communications
DOI 10.1038/s41467-024-48592-8PMC PMC11166925

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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.

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References 78 · Cited by 30

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Metadata

Authors
van Rhijn, N., Zhao, C., Al-Furaiji, N., Storer, I. S. R., Valero, C., Gago, S., Chown, H., Baldin, C., Grant, R.-F., Bin Shuraym, H., Ivanova, L., Kniemeyer, O., Krüger, T., Bignell, E., Goldman, G. H., Amich, J., Delneri, D., Bowyer, P., Brakhage, A. A., Haas, H., & Bromley, M. J.
Affiliations
  • University of Manchester (GB)
  • Innsbruck Medical University (AT)
  • Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
  • University of Exeter (GB)
  • Universidade de São Paulo (BR)
  • Instituto de Salud Carlos III (ES)
  • King Saud bin Abdulaziz University for Health Sciences (SA)
Corresponding author
Bromley, Michael J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-11
Volume
15
Issue
1
Pages
4984-4984
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-48592-8
PMC
PMC11166925
OpenAlex
W4399528542
Cited by
30
References
78
Citations by year
2026: 8 · 2025: 17 · 2024: 4
FWCI
3.94
Type
journal article
Language
en
Update notices
correction (2024-08-20)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, cc-by)
  • e-space (Manchester Metropolitan University) (submittedVersion, cc-by)
  • e-space (Manchester Metropolitan University) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • UEA Digital Repository (University of East Anglia) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
Funders
Wellcome Trust (208396/Z/17/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
Keywords
Aspergillus fumigatus, DYRK kinases, azole resistance, antifungal drug targets, knockout mutants, fungal pathogenicity, pulmonary infection, stress response

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