title: Sensitisation of an Azole-Resistant Aspergillus fumigatus Strain containing the Cyp51A-Related Mutation by Deleting the SrbA Gene.
abstract: Azoles are widely used for controlling fungal growth in both agricultural and medical settings. The target protein of azoles is CYP51, a lanosterol 14-α-demethylase involved in the biosynthesis of ergosterol. Recently, a novel azole resistance mechanism has arisen in pathogenic fungal species Aspergillus fumigatus. Resistant strains contain a 34-bp or 46-bp tandem repeat (TR) in the promoter of cyp51A, and have disseminated globally in a short period of time. In this study, we investigated whether an azole-resistant strain with a 46-bp TR (TR46/Y121F/T289A) could be sensitised to azoles by deletion of srbA, encoding a direct regulator of cyp51A. The loss of SrbA did not affect colony growth or conidia production, but decreased expression of cyp51A. The srbA deletion strain showed hyper-susceptibility to medical azoles as well as azole fungicides, while its sensitivity to non-azole fungicides was unchanged. This is the first demonstration that deletion of a regulator of cyp51A can sensitise an azole-resistant A. fumigatus strain. This finding may assist in the development of new drugs to help combat life-threatening azole-resistant fungal pathogens.
authors.affiliation: Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba City, 260-8673, Chiba, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hagiwara
authors.affiliation: Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba City, 260-8673, Chiba, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba City, 260-8673, Chiba, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kamei
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics*; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics*; D005659:Fungicides, Industrial / Q000494:pharmacology*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000235:genetics*; D005800:Genes, Fungal; D009154:Mutation; D010100:Oxygen / Q000494:pharmacology; D020080:Tandem Repeat Sequences; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D005659:Fungicides, Industrial; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D010100:Oxygen