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

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. Kowalski, Shriya Raj, Sanjoy Paul, Peter Cook, Josie E. Parker, Steve Kelly, Robert A. Cramer, Jean-Paul Latgé, Scott Moye-Rowley, Elaine Bignell, Paul Bowyer () and Michael J. Bromley ()
Additional contact information
Takanori Furukawa: University of Manchester
Norman van Rhijn: University of Manchester
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
Rachael Fortune-Grant: University of Manchester
Sayema Rahman: University of Manchester
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
Paul Bowyer: University of Manchester
Michael J. Bromley: University of Manchester

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14191-1

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