Journal article
The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
Nature communications, Vol.11(1), pp.427-427
01/22/2020
DOI: 10.1038/s41467-019-14191-1
PMCID: PMC7194077
PMID: 31969561
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.
Details
- Title: Subtitle
- The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
- Creators
- Takanori Furukawa - Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UKNorman van Rhijn - University of ManchesterMarcin Fraczek - University of ManchesterFabio Gsaller - University of ManchesterEmma Davies - University of ManchesterPaul Carr - University of ManchesterSara Gago - University of ManchesterRachael Fortune-Grant - University of ManchesterSayema Rahman - University of ManchesterJane Mabey Gilsenan - University of ManchesterEmma Houlder - Manchester Academic Health Science CentreCaitlin H Kowalski - Dartmouth CollegeShriya Raj - Institut PasteurSanjoy Paul - University of IowaPeter Cook - Manchester Academic Health Science CentreJosie E Parker - Swansea UniversitySteve Kelly - Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, Wales, SA2 8PP, UKRobert A Cramer - Dartmouth CollegeJean-Paul Latgé - Institut PasteurScott Moye-Rowley - University of IowaElaine Bignell - University of ManchesterPaul Bowyer - University of ManchesterMichael J Bromley - University of Manchester
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.11(1), pp.427-427
- DOI
- 10.1038/s41467-019-14191-1
- PMID
- 31969561
- PMCID
- PMC7194077
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- R01 AI130128 / NIAID NIH HHS Wellcome Trust R01 AI143198 / NIAID NIH HHS MR/M02010X/1 / Medical Research Council R01 AI081838 / NIAID NIH HHS
- Language
- English
- Date published
- 01/22/2020
- Academic Unit
- Molecular Physiology and Biophysics; Internal Medicine
- Record Identifier
- 9984297610002771
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