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A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
Nature Communications, Volume: 15, Issue: 1
Swansea University Author: Steven Kelly
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DOI (Published version): 10.1038/s41467-024-48029-2
Abstract
Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B,...
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ISSN: | 2041-1723 |
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Springer Science and Business Media LLC
2024
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Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance.</abstract><type>Journal Article</type><journal>Nature Communications</journal><volume>15</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2041-1723</issnElectronic><keywords/><publishedDay>29</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-04-29</publishedDate><doi>10.1038/s41467-024-48029-2</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This work was supported by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant R01 AI143197 (J.R.F./P.D.R.) and grant U19 AI110820 (V.M.B.). 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v2 66425 2024-05-15 A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2024-05-15 Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance. Journal Article Nature Communications 15 1 Springer Science and Business Media LLC 2041-1723 29 4 2024 2024-04-29 10.1038/s41467-024-48029-2 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee This work was supported by the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant R01 AI143197 (J.R.F./P.D.R.) and grant U19 AI110820 (V.M.B.). We are grateful for the SJCRH Hartwell Center (supported in part by the ALSAC and the National Cancer Institute grant P30 CA021765) for their expertize in generating the whole genome sequencing data. 2024-06-18T20:28:21.1811068 2024-05-15T08:46:24.5659186 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Jeffrey M. Rybak 0000-0002-9317-0935 1 Jinhong Xie 0000-0002-8994-6606 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 Ana C. O. Souza 0000-0002-9639-1207 8 Amol C. Shetty 0000-0001-8790-7649 9 Carrie McCracken 10 Vincent M. Bruno 11 Josie E. Parker 0000-0002-3855-4194 12 Steven Kelly 13 Hannah M. Snell 0009-0006-4308-0292 14 Christina A. Cuomo 0000-0002-5778-960x 15 P. David Rogers 16 Jarrod R. Fortwendel 0000-0003-2301-4272 17 66425__30373__3b5a2066d8fa42e480e504c6848b2934.pdf 66425.pdf 2024-05-15T08:49:25.2519181 Output 9352596 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng https://creativecommons.org/licenses/by/4.0/ |
title |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
spellingShingle |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 Steven Kelly |
title_short |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
title_full |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
title_fullStr |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
title_full_unstemmed |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
title_sort |
A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1 |
author_id_str_mv |
b17cebaf09b4d737b9378a3581e3de93 |
author_id_fullname_str_mv |
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly |
author |
Steven Kelly |
author2 |
Jeffrey M. Rybak Jinhong Xie Adela Martin-Vicente Xabier Guruceaga Harrison I. Thorn Ashley V. Nywening Wenbo Ge Ana C. O. Souza Amol C. Shetty Carrie McCracken Vincent M. Bruno Josie E. Parker Steven Kelly Hannah M. Snell Christina A. Cuomo P. David Rogers Jarrod R. Fortwendel |
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Journal article |
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Nature Communications |
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15 |
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2024 |
institution |
Swansea University |
issn |
2041-1723 |
doi_str_mv |
10.1038/s41467-024-48029-2 |
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Springer Science and Business Media LLC |
college_str |
Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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description |
Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance. |
published_date |
2024-04-29T20:28:19Z |
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1802228360488681472 |
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11.028886 |