Mevalonate governs interdependency of ergosterol and siderophore biosyntheses in the fungal pathogen Aspergillus fumigatus
Open accessAbstract
Aspergillus fumigatus is the most common airborne fungal pathogen for humans. In this mold, iron starvation induces production of the siderophore triacetylfusarinine C (TAFC). Here we demonstrate a link between TAFC and ergosterol biosynthetic pathways, which are both critical for virulence and treatment of fungal infections. Consistent with mevalonate being a limiting prerequisite for TAFC biosynthesis, we observed increased expression of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase (Hmg1) under iron starvation, reduced TAFC biosynthesis following lovastatin-mediated Hmg1 inhibition, and increased TAFC biosynthesis following Hmg1 overexpression. We identified enzymes, the acyl-CoA ligase SidI and the enoyl-CoA hydratase SidH, linking biosynthesis of mevalonate and TAFC, deficiency of which under iron starvation impaired TAFC biosynthesis, growth, oxidative stress resistance, and murine virulence. Moreover, inactivation of these enzymes alleviated TAFC-derived biosynthetic demand for mevalonate, as evidenced by increased resistance to lovastatin. Concordant with bilateral demand for mevalonate, iron starvation decreased the ergosterol content and composition, a phenotype that is mitigated in TAFC-lacking mutants.
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Various statins have been reported to inhibit the growth of Aspergillus, Zygomycete, Cryptococcus, and Candida species including Candida albicans.
“Various statins have been reported to inhibit the growth of Aspergillus (Macreadie et al., 2006; Yasmin et al., 2012), Zygomycete (Roze and Linz, 1998), Cryptococcus (Chin et al., 1997), and Candida species including Candida albicans (Chin et al., 1997; Song et al., 2003).”
From Atorvastatin Reduces the Survival of Candida albicans-Infected BALB/c Mice (2015) · cites this paper as Yasmin et al., 2012
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- Authors
- Yasmin, S., Alcazar-Fuoli, L., Gründlinger, M., Puempel, T., Cairns, T., Blatzer, M., Lopez, J. F., Grimalt, J. O., Bignell, E., & Haas, H.
- Affiliations
- Innsbruck Medical University (AT)
- Microbiology Section, Imperial College London, London SW7 2AZ, United Kingdom;
- Department of Microbiology, University of Innsbruck, A-6020 Innsbruck, Austria; and
- Imperial College London (GB)
- Department of Environmental Chemistry, Institute of Environmental Assessment and Water Studies, Jordi Girona, 08034 Barcelona, Catalonia Spain
- Institute of Environmental Assessment and Water Research (ES)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-11-21
- Volume
- 109
- Issue
- 8
- Pages
- E497-504
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3286978
- OpenAlex
- W2046068423
- Cited by
- 126
- References
- 58
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 15 · 2022: 7 · 2021: 13 · 2020: 5 · 2019: 11 · 2018: 9 · 2017: 4 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 9 · 2012: 7
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Austrian Science Fund
- Biotechnology and Biological Sciences Research Council (BB/G009619/1)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- Aspergillus fumigatus, mevalonate, ergosterol biosynthesis, siderophore biosynthesis, iron starvation, HMG-CoA reductase, HMG1, Sidi, SIDH, lovastatin, fungal virulence, oxidative stress resistance, fungal pathogens
- MeSH terms
- Iron Deficiencies, Amphotericin B, Animals, Aspergillus fumigatus, Enoyl-CoA Hydratase, Ergosterol, Ferric Compounds, Genes, Fungal, Hydroxamic Acids, Hydroxymethylglutaryl CoA Reductases, Ligases, Lovastatin, Mevalonic Acid, Microbial Sensitivity Tests, Pyrimidines, Triazoles, Virulence, Up-Regulation, Gene Expression Regulation, Fungal, Gene Expression Regulation, Enzymologic, Siderophores, Gene Deletion, Oxidative Stress, Biomass, Gene Silencing, Mice, Biosynthetic Pathways, Pulmonary Aspergillosis, Voriconazole
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