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

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dc.contributor.authorRybak, Jeffrey M.
dc.contributor.authorXie, Jinhong
dc.contributor.authorMartín-Vicente, Adela
dc.contributor.authorGuruceaga Sierra, Xabier
dc.contributor.authorThorn, Harrison I.
dc.contributor.authorNywening, Ashley V.
dc.contributor.authorGe, Wenbo
dc.contributor.authorSouza, Ana Camila Oliveira
dc.contributor.authorShetty, Amol C.
dc.contributor.authorMcCracken, Carrie
dc.contributor.authorBruno, Vincent M.
dc.contributor.authorParker, Josie E.
dc.contributor.authorKelly, Steven L.
dc.contributor.authorSnell, Hannah M.
dc.contributor.authorCuomo, Christina A.
dc.contributor.authorRogers, P. David
dc.contributor.authorFortwendel, Jarrod R.
dc.contributor.departmentAgronomía, Biotecnología y Alimentaciónes_ES
dc.contributor.departmentAgronomia, Bioteknologia eta Elikaduraeu
dc.date.accessioned2024-12-04T11:58:10Z
dc.date.available2024-12-04T11:58:10Z
dc.date.issued2024-04-29
dc.date.updated2024-12-04T11:52:42Z
dc.description.abstractTriazole 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-¿-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.en
dc.description.sponsorshipThis 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.).
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.identifier.citationRybak, J. M., Xie, J., Martin-Vicente, A., Guruceaga, X., Thorn, H. I., Nywening, A. V. Ge, W., Souza, A. C. O., Shetty, A. C., McCracken, C., Bruno, V. M., Parker, J. E., Kelly, S. L., Snell, H. M., Cuomo, C. A., Rogers, P. D., Fortwendel, J. R. (2024). A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1. Nature Communications, 15, 1-16. https://doi.org/10.1038/s41467-024-48029-2.
dc.identifier.doi10.1038/s41467-024-48029-2
dc.identifier.issn2041-1723
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/52643
dc.language.isoeng
dc.publisherSpringer Nature
dc.relation.ispartofNature Communications (2024), vol. 15, núm. 3642
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-024-48029-2
dc.rights© The author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectTriazole antifungalsen
dc.subjectErgosterol biosynthesisen
dc.subjectHMG-CoA reductaseen
dc.subjectDrug resistanceen
dc.titleA secondary mechanism of action for triazole antifungals in aspergillus fumigatus mediated by hmg1en
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationa3a61d21-1d9e-444a-b472-bf213d85d3b7
relation.isAuthorOfPublication.latestForDiscoverya3a61d21-1d9e-444a-b472-bf213d85d3b7

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