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Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure

Arturo Luna-Tapia, Josie Parker, Steven Kelly Orcid Logo, Glen E. Palmer

Antimicrobial Agents and Chemotherapy, Volume: 65, Issue: 12

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/aac.01044-21

Abstract

The azole antifungals inhibit sterol 14α-demethylase (S14DM), leading to depletion of cellular ergosterol and the synthesis of an aberrant sterol-diol that disrupts membrane function. In Candida albicans, sterol diol production is catalyzed by the C-5 sterol desaturase enzyme encoded by ERG3. Accord...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: American Society for Microbiology 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58450
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spelling 2021-11-18T14:29:02.3008980 v2 58450 2021-10-22 Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2021-10-22 FGMHL The azole antifungals inhibit sterol 14α-demethylase (S14DM), leading to depletion of cellular ergosterol and the synthesis of an aberrant sterol-diol that disrupts membrane function. In Candida albicans, sterol diol production is catalyzed by the C-5 sterol desaturase enzyme encoded by ERG3. Accordingly, mutations that inactivate ERG3 enable the fungus to grow in the presence of the azoles. The purpose of this study was to compare the propensity of C-5 sterol desaturases from different fungal pathogens to produce the toxic diol upon S14DM inhibition and thus contribute to antifungal efficacy. The coding sequences of ERG3 homologs from C. albicans (CaERG3), Candida glabrata (CgERG3), Candida auris (CaurERG3), Cryptococcus neoformans (CnERG3), Aspergillus fumigatus (AfERG3A-C) and Rhizopus delemar (RdERG3A/B) were expressed in a C. albicans erg3Δ/Δ mutant to facilitate comparative analysis. All but one of the Erg3p-like proteins (AfErg3C) at least partially restored sterol C-5 desaturase activity, and to corresponding degrees rescued the stress and hyphal growth defects of the C. albicans erg3Δ/Δ mutant - confirming functional equivalence. Each C-5 desaturase enzyme conferred markedly different responses to fluconazole exposure in terms of the minimal inhibitory concentration (MIC) and residual growth observed at supra-MIC concentrations. Upon fluconazole-mediated inhibition of S14DM, the strains expressing each homolog also produced varying levels of 14α-methylergosta-8,24(28)-dien-3β,6α-diol. The RdErg3A and AfErg3A proteins are notable for low levels of sterol diol production and failing to confer appreciable azole sensitivity upon the C. albicans erg3Δ/Δ mutant. These findings suggest that species-specific properties of C5-sterol desaturase may be an important determinant of intrinsic azole sensitivity. Journal Article Antimicrobial Agents and Chemotherapy 65 12 American Society for Microbiology 0066-4804 1098-6596 17 11 2021 2021-11-17 10.1128/aac.01044-21 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University National Institute Of Allergy And Infectious Diseases of the National Institutes of Health (USA) under Award Number R33AI127607 2021-11-18T14:29:02.3008980 2021-10-22T10:55:56.8632904 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Arturo Luna-Tapia 1 Josie Parker 2 Steven Kelly 0000-0001-7991-5040 3 Glen E. Palmer 4 58450__21365__ddd1a3987eac43b7b3e620174e05c3e1.pdf 58450.AAM from Word.pdf 2021-10-29T11:16:42.8518149 Output 840638 application/pdf Accepted Manuscript true 2022-05-17T00:00:00.0000000 true eng
title Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
spellingShingle Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
Josie Parker
Steven Kelly
title_short Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
title_full Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
title_fullStr Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
title_full_unstemmed Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
title_sort Species-Specific Differences in C-5 Sterol Desaturase Function Influence the Outcome of Azole Antifungal Exposure
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Josie Parker
Steven Kelly
author2 Arturo Luna-Tapia
Josie Parker
Steven Kelly
Glen E. Palmer
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container_title Antimicrobial Agents and Chemotherapy
container_volume 65
container_issue 12
publishDate 2021
institution Swansea University
issn 0066-4804
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doi_str_mv 10.1128/aac.01044-21
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 - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description The azole antifungals inhibit sterol 14α-demethylase (S14DM), leading to depletion of cellular ergosterol and the synthesis of an aberrant sterol-diol that disrupts membrane function. In Candida albicans, sterol diol production is catalyzed by the C-5 sterol desaturase enzyme encoded by ERG3. Accordingly, mutations that inactivate ERG3 enable the fungus to grow in the presence of the azoles. The purpose of this study was to compare the propensity of C-5 sterol desaturases from different fungal pathogens to produce the toxic diol upon S14DM inhibition and thus contribute to antifungal efficacy. The coding sequences of ERG3 homologs from C. albicans (CaERG3), Candida glabrata (CgERG3), Candida auris (CaurERG3), Cryptococcus neoformans (CnERG3), Aspergillus fumigatus (AfERG3A-C) and Rhizopus delemar (RdERG3A/B) were expressed in a C. albicans erg3Δ/Δ mutant to facilitate comparative analysis. All but one of the Erg3p-like proteins (AfErg3C) at least partially restored sterol C-5 desaturase activity, and to corresponding degrees rescued the stress and hyphal growth defects of the C. albicans erg3Δ/Δ mutant - confirming functional equivalence. Each C-5 desaturase enzyme conferred markedly different responses to fluconazole exposure in terms of the minimal inhibitory concentration (MIC) and residual growth observed at supra-MIC concentrations. Upon fluconazole-mediated inhibition of S14DM, the strains expressing each homolog also produced varying levels of 14α-methylergosta-8,24(28)-dien-3β,6α-diol. The RdErg3A and AfErg3A proteins are notable for low levels of sterol diol production and failing to confer appreciable azole sensitivity upon the C. albicans erg3Δ/Δ mutant. These findings suggest that species-specific properties of C5-sterol desaturase may be an important determinant of intrinsic azole sensitivity.
published_date 2021-11-17T04:14:59Z
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