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The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus

Author

Listed:
  • Takanori Furukawa

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Norman van Rhijn

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Marcin Fraczek

    (University of Manchester)

  • Fabio Gsaller

    (University of Manchester)

  • Emma Davies

    (University of Manchester)

  • Paul Carr

    (University of Manchester)

  • Sara Gago

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Rachael Fortune-Grant

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Sayema Rahman

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Jane Mabey Gilsenan

    (University of Manchester)

  • Emma Houlder

    (University of Manchester, Manchester Academic Health Science Centre)

  • Caitlin H. Kowalski

    (Geisel School of Medicine at Dartmouth)

  • Shriya Raj

    (Unité des Aspergillus, Institut Pasteur)

  • Sanjoy Paul

    (University of Iowa)

  • Peter Cook

    (University of Manchester, Manchester Academic Health Science Centre)

  • Josie E. Parker

    (Swansea University Medical School, Swansea University)

  • Steve Kelly

    (Swansea University Medical School, Swansea University)

  • Robert A. Cramer

    (Geisel School of Medicine at Dartmouth)

  • Jean-Paul Latgé

    (Unité des Aspergillus, Institut Pasteur)

  • Scott Moye-Rowley

    (University of Iowa)

  • Elaine Bignell

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Paul Bowyer

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

  • Michael J. Bromley

    (University of Manchester
    University of Manchester, Manchester Academic Health Science Centre)

Abstract

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity.

Suggested Citation

  • Takanori Furukawa & Norman van Rhijn & Marcin Fraczek & Fabio Gsaller & Emma Davies & Paul Carr & Sara Gago & Rachael Fortune-Grant & Sayema Rahman & Jane Mabey Gilsenan & Emma Houlder & Caitlin H. Ko, 2020. "The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14191-1
    DOI: 10.1038/s41467-019-14191-1
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    Cited by:

    1. Arnab Chakraborty & Liyanage D. Fernando & Wenxia Fang & Malitha C. Dickwella Widanage & Pingzhen Wei & Cheng Jin & Thierry Fontaine & Jean-Paul Latgé & Tuo Wang, 2021. "A molecular vision of fungal cell wall organization by functional genomics and solid-state NMR," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Jinhong Xie & Jeffrey M. Rybak & Adela Martin-Vicente & Xabier Guruceaga & Harrison I. Thorn & Ashley V. Nywening & Wenbo Ge & Josie E. Parker & Steven L. Kelly & P. David Rogers & Jarrod R. Fortwende, 2024. "The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Neil A. R. Gow & Carolyn Johnson & Judith Berman & Alix T. Coste & Christina A. Cuomo & David S. Perlin & Tihana Bicanic & Thomas S. Harrison & Nathan Wiederhold & Mike Bromley & Tom Chiller & Keegan , 2022. "The importance of antimicrobial resistance in medical mycology," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Paul Bowyer & Andrew Currin & Daniela Delneri & Marcin G. Fraczek, 2022. "Telomere-to-telomere genome sequence of the model mould pathogen Aspergillus fumigatus," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    5. 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 & Tho, 2024. "Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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