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Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility

Tomye L. Ollinger, Robert Zarnowski Orcid Logo, Josie E. Parker, Steven Kelly, David R. Andes Orcid Logo, Mark A. Stamnes, Damian J. Krysan Orcid Logo

Antimicrobial Agents and Chemotherapy, Start page: e01294-24

Swansea University Author: Steven Kelly

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DOI (Published version): 10.1128/aac.01294-24

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...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: American Society for Microbiology 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa68650
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spelling 2025-01-03T15:05:18.3083166 v2 68650 2025-01-03 Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2025-01-03 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. Journal Article Antimicrobial Agents and Chemotherapy 0 e01294-24 American Society for Microbiology 0066-4804 1098-6596 Candida glabrata, antifungal resistance, azole, mitochondrial metabolism 23 12 2024 2024-12-23 10.1128/aac.01294-24 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee 2025-01-03T15:05:18.3083166 2025-01-03T14:54:48.1394295 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Tomye L. Ollinger 1 Robert Zarnowski 0000-0001-6343-1500 2 Josie E. Parker 3 Steven Kelly 4 David R. Andes 0000-0002-7927-9950 5 Mark A. Stamnes 6 Damian J. Krysan 0000-0001-6330-3365 7
title Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
spellingShingle Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
Steven Kelly
title_short Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
title_full Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
title_fullStr Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
title_full_unstemmed Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
title_sort Genetic interaction analysis of Candida glabrata transcription factors CST6 and UPC2A in the regulation of respiration and fluconazole susceptibility
author_id_str_mv b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Steven Kelly
author2 Tomye L. Ollinger
Robert Zarnowski
Josie E. Parker
Steven Kelly
David R. Andes
Mark A. Stamnes
Damian J. Krysan
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 0
container_start_page e01294-24
publishDate 2024
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/aac.01294-24
publisher American Society for Microbiology
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description 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.
published_date 2024-12-23T14:39:25Z
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