A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1

Rybak, Jeffrey M.; Xie, Jinhong; Martin-Vicente, Adela; Guruceaga, Xabier; Thorn, Harrison I.; Nywening, Ashley V.; Ge, Wenbo; O., Ana C.; Shetty, Amol C.; McCracken, Carrie; Bruno, Vincent M.; Parker, Josie E.; Kelly, Steven; Snell, Hannah M.; Cuomo, Christina A.; Rogers, P. David; Fortwendel, Jarrod R.

doi:10.1038/s41467-024-48029-2

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A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1

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

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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Published in:	Nature Communications
ISSN:	2041-1723
Published:	Springer Science and Business Media LLC 2024
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa66425
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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. 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spelling	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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container_title	Nature Communications
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publishDate	2024
institution	Swansea University
issn	2041-1723
doi_str_mv	10.1038/s41467-024-48029-2
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
document_store_str	1
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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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A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1

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