TY - JOUR
T1 - The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
AU - Furukawa, Takanori
AU - van Rhijn, Norman
AU - Fraczek, Marcin
AU - Gsaller, Fabio
AU - Davies, Emma
AU - Carr, Paul
AU - Gago, Sara
AU - Fortune-Grant, Rachael
AU - Rahman, Sayema
AU - Gilsenan, Jane Mabey
AU - Houlder, Emma
AU - Kowalski, Caitlin H.
AU - Raj, Shriya
AU - Paul, Sanjoy
AU - Cook, Peter
AU - Parker, Josie E.
AU - Kelly, Steve
AU - Cramer, Robert A.
AU - Latgé, Jean Paul
AU - Moye-Rowley, Scott
AU - Bignell, Elaine
AU - Bowyer, Paul
AU - Bromley, Michael J.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078185772&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-14191-1
DO - 10.1038/s41467-019-14191-1
M3 - Article
C2 - 31969561
AN - SCOPUS:85078185772
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 427
ER -