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A secondary mechanism of action for triazole antifungals in Aspergillus fumigatus mediated by hmg1
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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,...
| 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/cronfa66425 |
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| 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, 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. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
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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. |
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