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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species

Jinhong Xie Orcid Logo, Jeffrey M. Rybak Orcid Logo, Adela Martin-Vicente, Xabier Guruceaga Orcid Logo, Harrison I. Thorn Orcid Logo, Ashley V. Nywening, Wenbo Ge, Josie E. Parker Orcid Logo, Steven Kelly, P. David Rogers, Jarrod R. Fortwendel Orcid Logo

Nature Communications, Volume: 15, Issue: 1

Swansea University Author: Steven Kelly

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DOI (Published version): 10.1038/s41467-024-48767-3

Abstract

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa67192
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spelling 2024-08-29T13:54:27.0012552 v2 67192 2024-07-26 The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2024-07-26 Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target. Journal Article Nature Communications 15 1 Springer Science and Business Media LLC 2041-1723 20 5 2024 2024-05-20 10.1038/s41467-024-48767-3 COLLEGE NANME COLLEGE CODE Swansea University This work was supported by National Institutes of Health (NIH) / National Institute of Allergy and Infectious Diseases (NIAID) grants R01 AI158442 (JRF) and R01 AI143197 (JRF/PDR). The authors would also like to thank Nathan P. Wiederhold, PharmD at the Fungus Testing laboratory for providing the A. lentulus isolate used in this study. 2024-08-29T13:54:27.0012552 2024-07-26T12:14:28.0127252 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Jinhong Xie 0000-0002-8994-6606 1 Jeffrey M. Rybak 0000-0002-9317-0935 2 Adela Martin-Vicente 3 Xabier Guruceaga 0000-0003-3258-2482 4 Harrison I. Thorn 0009-0003-2546-8400 5 Ashley V. Nywening 6 Wenbo Ge 7 Josie E. Parker 0000-0002-3855-4194 8 Steven Kelly 9 P. David Rogers 10 Jarrod R. Fortwendel 0000-0003-2301-4272 11 67192__31174__360561c40d7649c0bd8d02d1fa51c4ca.pdf 67192.VoR.pdf 2024-08-29T13:40:22.7295367 Output 4584898 application/pdf Version of Record true © The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
spellingShingle The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
Steven Kelly
title_short The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_full The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_fullStr The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_full_unstemmed The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
title_sort The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
author_id_str_mv b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Steven Kelly
author2 Jinhong Xie
Jeffrey M. Rybak
Adela Martin-Vicente
Xabier Guruceaga
Harrison I. Thorn
Ashley V. Nywening
Wenbo Ge
Josie E. Parker
Steven Kelly
P. David Rogers
Jarrod R. Fortwendel
format Journal article
container_title Nature Communications
container_volume 15
container_issue 1
publishDate 2024
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-024-48767-3
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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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 Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus, A. terreus, and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6-repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target.
published_date 2024-05-20T05:14:55Z
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