The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
Open Access
- 22 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-16
- https://doi.org/10.1038/s41467-019-14191-1
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.This publication has 85 references indexed in Scilit:
- Amphotericin primarily kills yeast by simply binding ergosterolProceedings of the National Academy of Sciences of the United States of America, 2012
- MEME-ChIP: motif analysis of large DNA datasetsBioinformatics, 2011
- Evolution of Transcription Networks — Lessons from YeastsCurrent Biology, 2010
- BEDTools: a flexible suite of utilities for comparing genomic featuresBioinformatics, 2010
- Cross‐species chemogenomic profiling reveals evolutionarily conserved drug mode of actionMolecular Systems Biology, 2010
- The Three Fungal Transmembrane Nuclear Pore Complex Proteins ofAspergillus nidulansAre Dispensable in the Presence of an Intact An-Nup84-120 ComplexMolecular Biology of the Cell, 2009
- Global distribution of negative cofactor 2 subunit-α on human promotersProceedings of the National Academy of Sciences of the United States of America, 2007
- Genomic analysis of the hierarchical structure of regulatory networksProceedings of the National Academy of Sciences of the United States of America, 2006
- A high-throughput gene knockout procedure for Neurospora reveals functions for multiple transcription factorsProceedings of the National Academy of Sciences of the United States of America, 2006
- Functional profiling of the Saccharomyces cerevisiae genomeNature, 2002