title: Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.
abstract: Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette) efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.
authors.affiliation: College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Guan
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jiang
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Guo
authors.forename: Eugenio
authors.initials: E
authors.lastname: Mancera
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Yudong
authors.initials: Y
authors.lastname: Li
authors.forename: Lars
authors.initials: L
authors.lastname: Steinmetz
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Li
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Gu
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D009154:Mutation; D012440:Saccharomyces / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D013045:Species Specificity
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins