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

Furukawa, Takanori, van Rhijn, Norman, Fraczek, Marcin, Gsaller, Fabio, Davies, Emma, Carr, Paul, Gago, Sara, Fortune-Grant, Rachael, Rahman, Sayema, Gilsenan, Jane Mabey, Houlder, Emma, Kowalski, Caitlin H., Raj, Shriya, Paul, Sanjoy, Cook, Peter, Parker, Josie E., Kelly, Steve, Cramer, Robert A., Latgé, Jean-Paul, Moye-Rowley, Scott, Bignell, Elaine, Bowyer, Paul and Bromley, Michael J. 2020. The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus. Nature Communications 11 (1) , 427. 10.1038/s41467-019-14191-1

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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.

Item Type:	Article
Date Type:	Published Online
Schools:	Biosciences
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	8 July 2022
Date of Acceptance:	13 December 2019
Last Modified:	28 May 2023 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/151172

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