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

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The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-22 , DOI: 10.1038/s41467-019-14191-1
Takanori Furukawa _{1,

2} , Norman van Rhijn _{1,

2} , Marcin Fraczek ₁ , Fabio Gsaller ₁ , Emma Davies ₁ , Paul Carr ₁ , Sara Gago _{1,

2} , Rachael Fortune-Grant _{1,

2} , Sayema Rahman _{1,

2} , Jane Mabey Gilsenan ₁ , Emma Houlder ₂ , Caitlin H Kowalski ₃ , Shriya Raj ₄ , Sanjoy Paul ₅ , Peter Cook ₂ , Josie E Parker ₆ , Steve Kelly ₆ , Robert A Cramer ₃ , Jean-Paul Latgé ₄ , Scott Moye-Rowley ₅ , Elaine Bignell _{1,

2} , Paul Bowyer _{1,

2} , Michael J Bromley _{1,

2}

Affiliation

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.

中文翻译：

负辅因子 2 复合物是烟曲霉耐药性的关键调节因子。

抗真菌药耐药的频率，特别是对唑类麦角甾醇生物合成抑制剂的耐药性，是一个日益严重的全球健康问题。那些感染耐药菌株的人的存活率非常低。除了药物靶点的修饰之外，我们对真菌病原体烟曲霉中唑类抗性的分子基础的理解是有限的。我们推断，临床相关的抗真菌耐药性可能源于转录重新布线，在不降低致病性的情况下促进耐药性。在这里，我们报告了烟曲霉中转录调节因子的全基因组注释和 484 个转录因子无效突变体库的构建。

更新日期：2020-01-23

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