Mutations in hmg1 , Challenging the Paradigm of Clinical Triazole Resistance in Aspergillus fumigatus
Open accessAbstract
Aspergillus fumigatus is the predominant pathogen of invasive aspergillosis, a disease state credited with over 200,000 life-threatening infections annually. The triazole class of antifungals are clinically essential to the treatment of invasive aspergillosis. Unfortunately, resistance to the triazoles among A. fumigatus isolates is now increasingly reported worldwide. In this work, we challenge the current paradigm of clinical triazole resistance in A. fumigatus , by first demonstrating that previously characterized mechanisms of resistance have nominal impact on triazole susceptibility and subsequently identifying a novel mechanism of resistance with a profound impact on clinical triazole susceptibility. We demonstrate that mutations in the HMG-CoA reductase gene, hmg1 , are common among resistant clinical isolates and that hmg1 mutations confer resistance to all clinically available triazole antifungals.
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In Candida albicans and Aspergillus fumigatus, the Y132F substitution in CaERG11 or Y121F substitution in Afcyp51A confers increased resistance to all triazoles except posaconazole.
“In both Candida albicans and Aspergillus fumigatus, the mutation encoding a tyrosine to phenylalanine amino acid substitution at a specific residue localized to the sterol-demethylase catalytic domain (Y132F in C. albicans CaERG11 and Y121F in A. fumigatus Afcyp51A) confers increased resistance to all triazoles except for posaconazole (4–7).”
From Delineation of the Direct Contribution of Candida auris <i>ERG11</i> Mutations to Clinical Triazole Resistance (2021) · cites this paper as [6]
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References 48 · Cited by 130
- Authors
- Rybak, J. M., Ge, W., Wiederhold, N. P., Parker, J. E., Kelly, S. L., Rogers, P. D., & Fortwendel, J. R.
- Affiliations
- University of Tennessee Health Science Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Swansea University (GB)
- Corresponding author
- Fortwendel, Jarrod R.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-04-30
- Volume
- 10
- Issue
- 2
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6445940
- OpenAlex
- W2929562905
- Cited by
- 130
- References
- 48
- Citations by year
- 2026: 20 · 2025: 14 · 2024: 11 · 2023: 13 · 2022: 16 · 2021: 27 · 2020: 21 · 2019: 8
- FWCI
- 13.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01 A1058145, R01 AI106925)
- American College of Clinical Pharmacy Research Institute (Futures Grant)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Aspergillus fumigatus, triazole resistance, HMG1, HMG-CoA reductase, invasive aspergillosis, antifungal resistance mechanisms, clinical isolates
- MeSH terms
- Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Humans, Hydroxymethylglutaryl CoA Reductases, Triazoles, Drug Resistance, Fungal, Mutant Proteins
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