title: CDR4 is the major contributor to azole resistance among four Pdr5p-like ABC transporters in Neurospora crassa.
abstract: Pdr5p-like ABC transporters play a significant role in azole resistance in Saccharomyces cerevisiae and Candida spp. Most of filamentous fungal species have multiple Pdr5p homologues. In this study, phylogenic analysis identified that filamentous fungi have at least two phylogenically distant groups of Pdr5p homologues. One contains PMR1-like Pdr5p homologues while the other contains both AtrF-like and AtrB-like Pdr5p homologues. Neurospora crassa has a total of four genes encoding Pdr5p homologues including CDR4 (PMR1-like), ATRB (AtrB-like), and ATRF (AtrF-like) and ATRF-2 (AtrF-like). By analyzing the susceptibilities of their knockout mutants to azole drugs including ketoconazole, fluconazole, and itraconazole, we found that deletion of cdr4 increased the susceptibility to antifungal azoles. In contrast, neither single-gene nor triple-gene deletion of atrb, atrf, and atrf-2 could not alter the susceptibility to azoles. In addition, cdr4, but not other Pdr5p homologue-coding genes, responded transcriptionally to ketoconazole stress. Together with the previous findings in other fungal species, these results suggest that the PMR1-like but not the AtrF-like or AtrB-like Pdr5p homologues play a key role in antifungal azole resistance in filamentous fungi.
authors: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080, China.
authors: Yu
authors: Y
authors: Zhang
authors: Zhenying
authors: Z
authors: Zhang
authors: Xinyu
authors: X
authors: Zhang
authors: Hanxing
authors: H
authors: Zhang
authors: Xianyun
authors: X
authors: Sun
authors: Chengcheng
authors: C
authors: Hu
authors: Shaojie
authors: S
authors: Li
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D025141:Drug Resistance, Fungal; D015725:Fluconazole / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D017964:Itraconazole / Q000378:metabolism / Q000494:pharmacology*; D007654:Ketoconazole / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009492:Neurospora crassa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D005656:Fungal Proteins; D017964:Itraconazole; D015725:Fluconazole; D007654:Ketoconazole