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The sterol C-24 methyltransferase encoding gene, erg6, is essential for viability of Aspergillus species
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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
Nature Communications, Volume: 15, Issue: 1
Swansea University Author: Steven Kelly
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© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License.
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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...
| Published in: | Nature Communications |
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| 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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| 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, 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
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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. |
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1 |