Journal article
Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
Antimicrobial agents and chemotherapy, Vol.69(2), e01294-24
02/13/2025
DOI: 10.1128/aac.01294-24
PMCID: PMC11823675
PMID: 39714155
Abstract
Candida glabrata is the second most common cause of invasive candidiasis and is widely known to have reduced susceptibility to fluconazole relative to many other Candida spp. Upc2A is a transcription factor that regulates ergosterol biosynthesis gene expression under conditions of sterol stress such as azole drug treatment or hypoxia. Through an in vitro microevolution experiment, we found that loss-of-function mutants of the ATF/CREB transcription factor CST6 suppresses the fluconazole hyper-susceptibility of the upc2A∆ mutant. Here, we confirm that the cst6∆ upc2A∆ mutants are resistant to fluconazole but not to hypoxia relative to the upc2A∆ mutant. Sterol analysis of these mutants indicates that this suppression phenotype is not due to restoration of ergosterol levels in the cst6∆ upc2A∆ mutant. Furthermore, increased expression of CDR1, the efflux pump implicated in the vast majority of azole-resistant C. glabrata strains, does not account for the suppression phenotype. Instead, our data suggest that this effect is due in part to increased expression of the adhesin EPA3, which has been shown by others to reduce fluconazole susceptibility in C. glabrata. In addition, we find that loss of both UPC2A and CST6 reduces the expression of mitochondrial and respiratory genes and that this also contributes to the suppression phenotype as well as to the resistance of cst6∆ to fluconazole. These latter data further emphasize the connection between mitochondrial function and azole susceptibility.
Details
- Title: Subtitle
- Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
- Creators
- Tomye L. Ollinger - University of IowaRobert Zarnowski - University of Wisconsin–MadisonJosie E. Parker - Cardiff UniversitySteven L. Kelly - Swansea UniversityDavid R. Andes - University of Wisconsin–MadisonMark A. Stamnes - University of IowaDamian J. Krysan - University of Iowa
- Contributors
- Andreas H. Groll (Editor)
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.69(2), e01294-24
- DOI
- 10.1128/aac.01294-24
- PMID
- 39714155
- PMCID
- PMC11823675
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- American Society for Microbiology
- Number of pages
- 17
- Grant note
- Samuel J. Fomon Chair in Pulmonology/Allergy/Infectious Diseases at the University of Iowa
This work was supported in part by the Samuel J. Fomon Chair in Pulmonology/Allergy/Infectious Diseases at the University of Iowa (D.J.K.)
- Language
- English
- Electronic publication date
- 12/23/2024
- Date published
- 02/13/2025
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics); Internal Medicine
- Record Identifier
- 9984759116102771
Metrics
4 Record Views