Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole
Abstract
OBJECTIVES: Voriconazole, itraconazole and posaconazole are members of the azole family and widely used for the treatment of aspergillosis. They act by inhibiting the activity of the fungal Cyp51A enzyme. The emergence of environmental azole-resistant Aspergillus fumigatus strains raises major concerns for human health. METHODS: Recently, a new cyp51A-mediated resistance mechanism (namely TR46/Y121F/T289A) was described in clinical samples and patient-frequented environmental sites. In an azole-naive patient, we isolated an A. fumigatus strain that was not susceptible to voriconazole but was susceptible to itraconazole and posaconazole. RESULTS: A molecular analysis indicated a single Y121F substitution without the TR46 or T289A alterations, which to our knowledge has never been reported. Structure modelling and molecular dynamics offered an explanation for the resistance profile consistent with the structural differences between the three azoles. CONCLUSIONS: Taken together, these observations suggest an original mechanism conferring resistance to azoles mediated by cyp51A of environmental origin. This uncommon susceptibility pattern might represent a 'missing link' between the wild-type A. fumigatus and the fully azole-resistant strain harbouring the TR46/Y121F/T289A mutations.
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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 [7]
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Aspergillus fumigatus and Aspergillosis in 2019
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- Authors
- Lescar, J., Meyer, I., Akshita, K., Srinivasaraghavan, K., Verma, C., Palous, M., Mazier, D., Datry, A., & Fekkar, A.
- Affiliations
- Nanyang Technological University (SG)
- Assistance Publique – Hôpitaux de Paris (FR)
- Agency for Science, Technology and Research (SG)
- Université Paris Cité (FR)
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-08-13
- Volume
- 69
- Issue
- 12
- Pages
- 3244-3247
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2115118709
- Cited by
- 54
- References
- 22
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 4 · 2015: 4 · 2014: 1
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Aspergillus fumigatus, azole resistance, cyp51A, voriconazole resistance, aspergillosis, antifungal susceptibility
- MeSH terms
- Antifungal Agents, Aspergillus fumigatus, Cytochrome P-450 Enzyme System, DNA, Fungal, Fungal Proteins, Molecular Sequence Data, Triazoles, Sequence Analysis, DNA, Itraconazole, Mutation, Missense, Drug Resistance, Fungal, Voriconazole
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