SrbA and its Role in Mediating Azole Drug Resistance in Aspergillus fumigatus

Ref ID: 18349

Author:

Sara J.Blosser, Sven D.Willger, Robert A. Cramer Jr

Author address:

Department
of Immunology & Infectious Diseases, Montana State University, Bozeman, Montana, USA sara.wezensky@msu.montana.edu

Full conference title:

Asperfest 8

Abstract:

Deletion of the transcription factor SrbA results in complete growth inhibition under hypoxic conditions, avirulence in a murine model of Invasive
Aspergillosis (IA), and increased sensitivity of A. fumigatus to triazoles. The purpose of this study is to investigate the mechanism and role of SrbA in
mediating azole resistance. Azole drugs target ergosterol biosynthesis as their mechanism of action, and are the drug class of choice for treatment of IA.
Erg11 (cyp51), the target of triazoles, is a 14-demethylase, and two functional copies (A/B) are encoded in the A. fumigatus genome. Transcript analysis
shows down-regulation of Erg11A in the SrbA mutant, delta-srbA, suggesting regulation by this transcription factor. Induction of Erg11A in delta-srbA
by regulatable promoter replacement restores wild-type levels of Erg11A, and ameliorates the azole sensitivity phenotype observed in delta-srbA.
Repression of this construct restores azole sensitivity, demonstrating that Erg11A repression is partially or wholly responsible for the delta-srbA-azole
phenotype. As SrbA appears to regulate Erg11A and several other key enzymes in ergosterol biosynthesis, understanding the regulon of SrbA could be
vital in the development of higher-octane antifungals. Sterol intermediates in delta-srbA indicate a blockage in the Erg25 (C4-desaturase) enzymatic step,
which is compounded in the Erg11A-induced strain. Studies investigating the induction of Erg25A with Erg11A in the delta-srbA background are
underway.

Abstract Number: 27)

Conference Year: 2011

Link to conference website: NULL

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