The opposing roles of SrbA and the HapX/CCAAT binding complex in the regulation of sterol biosynthesis and azole tolerance in Aspergillus fumigatus

F. Gsallera, P. Hortschanskyb, T. Furukawaa, P.D. Carra, B. Rasha, J. Capillac, C. Müllerd, F. Bracherd, H. Haase, A.A Brakhageb,f and M.J. Bromleya

Author address: 

aDivision of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, GB bDepartment of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany cMicrobiology Unit, Medical School, Universitat Rovira i Virgili, Spain dDepartment of Pharmacy, Center for Drug Research, Ludwig-Maximilians University of Munich, Germany eDivision of Molecular Biology, Biocentre, Medical University of Innsbruck, Austria fInstitute for Microbiology, Friedrich Schiller University Jena, Jena, Germany

Abstract: 

Azole drugs selectively target fungal sterol biosynthesis and are critical to our antifungal therapeutic
arsenal. Resistance to this class of agents in the major human mould pathogen Aspergillus fumigatus is
reaching levels that suggest that they could be lost for clinical use. One family of pan-azole resistant
isolates, characterized by the presence of a tandem repeat of at least 34 bases (TR34) within the
promoter of sterol C14-demethylase encoding gene cyp51A dominates and is found globally. We
demonstrate the transcriptional mechanisms underpinning TR34 mediated resistance showing the repeat
is bound by both the sterol regulatory element binding protein SrbA, and the CCAAT binding complex
(CBC). We show that the CBC acts complementary to SrbA as a negative regulator of ergosterol
biosynthesis and TR34 driven overexpression of cyp51A results from effective duplication of SrbA but not
CBC binding sites leading us to suggest possible routes to tackle the problem of TR34 mediated
resistance.

2017

abstract No: 

25

Full conference title: 

The Fourteenth International Aspergillus Meeting, Asilomar Conference Center, Pacific Grove, CA, USA
    • Asperfest 14 (2017)