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

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.

Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast.

Gain-of-function mutations in the transcription factors Pdr1p and Pdr3p lead to the up-regulation of genes controlling plasma membrane properties. Pdr3p is involved in a retrograde response in which mitochondrial dysfunctions activate PDR5, a gene encoding an ABC membrane transporter. We carried out genome-wide analyses of the PDR3-controlled genes activated by the deletion of the mitochondrial DNA. We present evidence showing that PDR1 does not interfere with this PDR3 response. We also showed that the mitochondrially activated PDR3 response is highly sensitive to both yeast strain variations and carbon sources. These observations explain the apparent discrepancies in published studies and better describe the connections between the mitochondrial state and plasma membrane properties.