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

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Functional analysis of the Aspergillus fumigatus kinome reveals a DYRK kinase involved in septal plugging is a novel antifungal drug target

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Rhijn, Norman van, Zhao, Can, Al-Furaji, Narjes, Storer, Isabelle, Valero, Clara, Gago, Sara, Chown, Harry, Baldin, Clara, Fortune-Grant, Rachael, Shuraym, Hajer Bin, Ivanova, Lia, Kniemeyer, Olaf, Krüger, Thomas, Bignell, Elaine, Goldman, Gustavo, Amich, Jorge, Delneri, Daniela, Bowyer, Paul, Brakhage, Axel, Haas, Hubertus, Bromley, Michael·2023·Nature Communications
DOI 10.21203/rs.3.rs-2960526/v1PMC PMC11166925

Preprint — published as 10.1038/s41467-024-48592-8 · Paper page

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Abstract

More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. The azole class of antifungals represent first line therapeutics for most of these infections however resistance is rising. Identification of novel antifungal targets that, when inhibited, synergise with the azoles will aid the development of agents that can improve therapeutic outcomes and supress the emergence of resistance. As part of the A. fumigatus genome-wide knockout program (COFUN), we have completed the generation of a library that consists of 120 genetically barcoded null mutants in genes that encode the protein kinase cohort of A. fumigatus. We have employed a competitive fitness profiling approach (Bar-Seq), to identify targets which when deleted result in hypersensitivity to the azoles and fitness defects in a murine host. The most promising candidate from our screen is a previously uncharacterised DYRK kinase orthologous to Yak1 of Candida albicans, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. Here we show that the orthologue YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress via phosphorylation of the Woronin body tethering protein Lah. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and impacts growth in murine lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit Yak1 in C. albicans prevents stress mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.

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Metadata

Authors
Rhijn, N. V., Zhao, C., Al-Furaji, N., Storer, I., Valero, C., Gago, S., Chown, H., Baldin, C., Fortune-Grant, R., Shuraym, H. B., Ivanova, L., Kniemeyer, O., Krüger, T., Bignell, E., Goldman, G., Amich, J., Delneri, D., Bowyer, P., Brakhage, A., Haas, H., & Bromley, M.
Affiliations
  • University of Manchester
  • University of Manchester (GB)
  • Manchester Fungal Infection Group
  • Innsbruck Medical University (AT)
  • King Saud bin Abdulaziz University for Health Sciences (SA)
  • 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)
Corresponding author
Bromley, Michael
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-05-30
Volume
15
Issue
1
Pages
4984-4984
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-2960526/v1
PMC
PMC11166925
OpenAlex
W4399528542
Cited by
30
References
1
Citations by year
2026: 8 · 2025: 17 · 2024: 4 · 2023: 1
FWCI
3.94
Type
journal article
Language
en
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
  • Ministry of Higher Education and Scientific Research
  • Wellcome Trust (Z/17/Z, 219551/Z/19/Z, 208396/Z/17/Z)
  • Deutsche Forschungsgemeinschaft (210879364, FungiNet 124)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (21/04977-5, 2021/, 2020/01131-5, 2018/00715-3)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (301058/2019-9, 301058/2019-9 and 404735/2018-5, 404735/2018-5)
  • National Institutes of Health
  • Medical Research Council (MR/M02010X/1)
  • Leibniz-Gemeinschaft
  • National Institute of Allergy and Infectious Diseases (R01AI153356)
  • Edgewood Chemical Biological Center
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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