The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
Takanori Furukawa, Norman van Rhijn, Marcin G. Fraczek, Fabio Gsaller, Emma Davies, Paul Carr, Sara Gago, Rachael Fortune‐Grant, Sayema Rahman, Jane Mabey Gilsenan, Emma L. Houlder, Caitlin H. Kowalski, Shriya Raj, Sanjoy Paul, Peter C. Cook, Josie E. Parker, Steve L. Kelly, Robert A. Cramer, Jean‐Paul Latgé, W. Scott Moye‐Rowley, Elaine Bignell, Paul Bowyer, Michael Bromley
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.