A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence

Zhang, Jianhua; Snelders, Eveline; Zwaan, Bas J.; Schoustra, Sijmen E.; Meis, Jacques F.; van Dijk, Karin; Hagen, Ferry; van der Beek, Martha T.; Kampinga, Greetje A.; Zoll, Jan; Melchers, Willem J. G.; Verweij, Paul E.; Debets, Alfons J. M.

doi:10.1128/mbio.00791-17

Cited by 129Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence

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Zhang, Jianhua, Snelders, Eveline, Zwaan, Bas J., Schoustra, Sijmen E., Meis, Jacques F., van Dijk, Karin, Hagen, Ferry, van der Beek, Martha T. +5 more·2017·mBio

DOI 10.1128/mbio.00791-17PMC PMC5487732

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Abstract

ABSTRACT This study investigated the dynamics of Aspergillus fumigatus azole-resistant phenotypes in two compost heaps with contrasting azole exposures: azole free and azole exposed. After heat shock, to which sexual but not asexual spores are highly resistant, the azole-free compost yielded 98% (49/50) wild-type and 2% (1/50) azole-resistant isolates, whereas the azole-containing compost yielded 9% (4/45) wild-type and 91% (41/45) resistant isolates. From the latter compost, 80% (36/45) of the isolates contained the TR 46 /Y121F/T289A genotype, 2% (1/45) harbored the TR 46 /Y121F/M172I/T289A/G448S genotype, and 9% (4/45) had a novel pan-triazole-resistant mutation (TR 46 3 /Y121F/M172I/T289A/G448S) with a triple 46-bp promoter repeat. Subsequent screening of a representative set of clinical A. fumigatus isolates showed that the novel TR 46 3 mutant was already present in samples from three Dutch medical centers collected since 2012. Furthermore, a second new resistance mutation was found in this set that harbored four TR 46 repeats. Importantly, in the laboratory, we recovered the TR 46 3 mutation from a sexual cross between two TR 46 isolates from the same azole-containing compost, possibly through unequal crossing over between the double tandem repeats (TRs) during meiosis. This possible role of sexual reproduction in the emergence of the mutation was further implicated by the high level of genetic diversity of STR genotypes in the azole-containing compost. Our study confirms that azole resistance mutations continue to emerge in the environment and indicates compost containing azole residues as a possible hot spot. Better insight into the biology of environmental resistance selection is needed to retain the azole class for use in food production and treatment of Aspergillus diseases. IMPORTANCE Composting of organic matter containing azole residues might be important for resistance development and subsequent spread of resistance mutations in Aspergillus fumigatus . In this article, we show the dominance of azole-resistant A. fumigatus in azole-exposed compost and the discovery of a new resistance mutation with clinical relevance. Furthermore, our study indicates that current fungicide application is not sustainable as new resistance mutations continue to emerge, thereby threatening the use of triazoles in medicine. We provide evidence that the sexual part of the fungal life cycle may play a role in the emergence of resistance mutations because under laboratory conditions, we reconstructed the resistance mutation through sexual crossing of two azole-resistant A. fumigatus isolates derived from the same compost heap. Understanding the mechanisms of resistance selection in the environment is needed to design strategies against the accumulation of resistance mutations in order to retain the azole class for crop protection and treatment of Aspergillus diseases.

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Compost is one of the major sources of Aspergillus.
“As shown in some publications, compost is one of the major sources of Aspergillus [37].”
From Nationwide Survey about the Occurrence of Aspergillosis in Captive Penguins in Zoos and Aquariums in Japan (2023) · cites this paper as [37]
The Introduction (page not specified) describes compost as an important biological niche for A. fumigatus with high densities of spores, and the Results report A. fumigatus in samples from two compost heaps. The paper does not establish that compost is one of the major sources of Aspergillus generally; the Discussion says compost could be a source of resistant A. fumigatus. (LLM, conf=0.84)
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Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study
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Triazole resistance surveillance in Aspergillus fumigatus
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Molecular Tools for the Detection and Deduction of Azole Antifungal Drug Resistance Phenotypes in Aspergillus Species
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Aspergillus fumigatus and pan-azole resistance: who should be concerned?
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Evolution of antifungal resistance in the environment
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High Azole Resistance in Aspergillus fumigatus Isolates from Strawberry Fields, China, 2018
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In Vivo Selection of a Unique Tandem Repeat Mediated Azole Resistance Mechanism (TR120) inAspergillus fumigatus cyp51A, Denmark
Hare, R. K., Gertsen, J. B., Astvad, K. M. T., Degn, K., Løkke, A., Stegger, M., Andersen, P. S., Kristensen, L., & Arendrup, M. C. (2019) · Emerging infectious diseases · doi:10.3201/eid2503.180297 · Cited by 54 · see citing works
The fading boundaries between patient and environmental routes of triazole resistance selection in Aspergillus fumigatus
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Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance
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Collateral consequences of agricultural fungicides on pathogenic yeasts: A One Health perspective to tackle azole resistance
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Genomic Diversity of Azole-Resistant Aspergillus fumigatus in the United States
Etienne, K. A., Berkow, E. L., Gade, L., Nunnally, N., Lockhart, S. R., Beer, K., Jordan, I. K., Rishishwar, L., & Litvintseva, A. P. (2021) · mBio · doi:10.1128/mbio.01803-21 · Cited by 48 · see citing works
Prevalence, mechanisms and genetic relatedness of the human pathogenic fungus Aspergillus fumigatus exhibiting resistance to medical azoles in the environment of Taiwan
Wang, H., Huang, J., Lin, Y., Chen, Y., Hsieh, M., Choi, P., Lo, H., Liu, W., Hsu, C., Shih, H., et al. (2017) · Environmental Microbiology · doi:10.1111/1462-2920.13988 · Cited by 47 · see citing works
Molecular Detection of Azole-Resistant Aspergillus fumigatus in Clinical Samples
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Fungicide-driven alterations in azole-resistantAspergillus fumigatusare related to vegetable crops in Colombia, South America
Álvarez, C., Lavergne, R., Hagen, F., Morio, F., Meis, J. F. G. M., & Pape, P. L. (2019) · Mycologia · doi:10.1080/00275514.2018.1557796 · Cited by 45 · see citing works
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Horizontal Gene Transfer of Triazole Resistance in Aspergillus fumigatus
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Exploring the molecular mechanism of azole resistance in Aspergillus fumigatus
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Azole‐resistant Aspergillus fumigatus as an emerging worldwide pathogen
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Surveillance for azole resistance in clinical and environmental isolates of Aspergillus fumigatus in Australia and cyp51A homology modelling of azole-resistant isolates
Talbot, J. J., Subedi, S., Halliday, C. L., Hibbs, D. E., Lai, F., López-Ruiz, F. J., Harper, L., Park, R., Cuddy, W. S., Biswas, C., et al. (2018) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dky187 · Cited by 41 · see citing works
Prospective multicenter surveillance of clinically isolated Aspergillus species revealed azole-resistant Aspergillus fumigatus isolates with TR34/L98H mutation in the Kyoto and Shiga regions of Japan
Tsuchido, Y., Tanaka, M., Nakano, S., Yamamoto, M., Matsumura, Y., & Nagao, M. (2019) · Medical Mycology · doi:10.1093/mmy/myz003 · Cited by 39 · see citing works
Phenotypic plasticity and the evolution of azole resistance in Aspergillus fumigatus; an expression profile of clinical isolates upon exposure to itraconazole
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Species Distribution and Antifungal Susceptibilities of Aspergillus Section Fumigati Isolates in Clinical Samples from the United States
Badali, H., Cañete-Gibas, C. F., McCarthy, D. I., Patterson, H. P., Sanders, C. J., David, M. P., Mele, J., Fan, H., & Wiederhold, N. P. (2022) · Journal of Clinical Microbiology · doi:10.1128/jcm.00280-22 · Cited by 36 · see citing works
First azole‐resistant Aspergillus fumigatus isolates with the environmental TR46/Y121F/T289A mutation in Iran
Ahangarkani, F., Puts, Y., Nabili, M., Khodavaisy, S., Moazeni, M., Salehi, Z., Kargar, M. L., Badali, H., & Meis, J. F. G. M. (2020) · Mycoses · doi:10.1111/myc.13064 · Cited by 35 · see citing works
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Dynamics of Aspergillus fumigatus in Azole Fungicide-Containing Plant Waste in the Netherlands (2016–2017)
Zhang, J., López-Jiménez, L., Snelders, E., Debets, A. J. M., Rietveld, A. G., Zwaan, B. J., Verweij, P. E., & Schoustra, S. E. (2020) · Applied and Environmental Microbiology · doi:10.1128/aem.02295-20 · Cited by 35 · see citing works
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Characteristics of azole-resistant Aspergillus fumigatus attached to agricultural products imported to Japan
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Azole-Resistant Aspergillus fumigatus Among Danish Cystic Fibrosis Patients: Increasing Prevalence and Dominance of TR34/L98H
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Recreation of in-host acquired single nucleotide polymorphisms by CRISPR-Cas9 reveals an uncharacterised gene playing a role in Aspergillus fumigatus azole resistance via a non-cyp51A mediated resistance mechanism
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The human fungal pathogen Aspergillus fumigatus can produce the highest known number of meiotic crossovers
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Azole resistance in Aspergillus species in Southern Taiwan: An epidemiological surveillance study
Chen, Y., Kuo, S., Wang, H., Wu, C., Lin, Y., Li, W., & Lee, C. (2019) · Mycoses · doi:10.1111/myc.13008 · Cited by 25 · see citing works
Dissection of the Activity of Agricultural Fungicides against Clinical Aspergillus Isolates with and without Environmentally and Medically Induced Azole Resistance
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Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus
Zhang, J., Snelders, E., Zwaan, B. J., Schoustra, S. E., Kuijper, E. J., Arendrup, M. C., Melchers, W. J. G., Verweij, P. E., & Debets, A. J. M. (2019) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2018.2886 · Cited by 22 · see citing works
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Five-Year Survey (2014 to 2018) of Azole Resistance in Environmental Aspergillus fumigatus Isolates from China
Cao, D., Wu, R., Dong, S., Wang, F., Ju, C., Yu, S., Xu, S., Fang, H., & Yu, Y. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00904-20 · Cited by 23 · see citing works
Azole-Resistance Development; How the Aspergillus fumigatus Lifecycle Defines the Potential for Adaptation
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Hospital Environment as a Source of Azole-Resistant Aspergillus fumigatus Strains with TR34/L98H and G448S Cyp51A Mutations
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Assessment of occupational exposure to azole resistant fungi in 10 Portuguese bakeries
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Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
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Understanding the clinical and environmental drivers of antifungal resistance in the One Health context
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Azole-Resistant Aspergillus fumigatus: Epidemiology, Diagnosis, and Treatment Considerations
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The Impact of Climate Change on Human Fungal Pathogen Distribution and Disease Incidence
Hamm, P. S., & Torres-Cruz, T. J. (2024) · Current Clinical Microbiology Reports · doi:10.1007/s40588-024-00224-x · Cited by 24 · see citing works
Clonal Expansion of Environmental Triazole Resistant Aspergillus fumigatus in Iran
Ahangarkani, F., Badali, H., Abbasi, K., Nabili, M., Khodavaisy, S., de Groot, T., & Meis, J. F. G. M. (2020) · Journal of Fungi · doi:10.3390/jof6040199 · Cited by 19 · see citing works
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Epidemiological Studies of Pan-Azole Resistant Aspergillus fumigatus Populations Sampled during Tulip Cultivation Show Clonal Expansion with Acquisition of Multi-Fungicide Resistance as Potential Driver
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Comprehensive Review of Environmental Surveillance for Azole-Resistant Aspergillus fumigatus: A Practical Roadmap for Hospital Clinicians and Infection Control Teams
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Crossover between the control of fungal pathogens in medicine and the wider environment, and the threat of antifungal resistance
Gisi, U. (2021) · Plant Pathology · doi:10.1111/ppa.13429 · Cited by 18 · see citing works
Genetic Diversity and Azole Resistance Among Natural Aspergillus fumigatus Populations in Yunnan, China
Zhou, D., Wang, R., Li, X., Peng, B., Yang, G., Zhang, K., Zhang, Y., & Xu, J. (2021) · Microbial Ecology · doi:10.1007/s00248-021-01804-w · Cited by 17 · see citing works
Selection and Amplification of Fungicide Resistance in Aspergillus fumigatus in Relation to DMI Fungicide Use in Agronomic Settings: Hotspots versus Coldspots
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Authors: Zhang, J., Snelders, E., Zwaan, B. J., Schoustra, S. E., Meis, J. F., van Dijk, K., Hagen, F., van der Beek, M. T., Kampinga, G. A., Zoll, J., Melchers, W. J. G., Verweij, P. E., & Debets, A. J. M.
Affiliations: Wageningen University & Research (NL)
Radboud University Nijmegen (NL)
Department of Medical Microbiology, VU University Medical Centre, Amsterdam, The Netherlands
Department of Medical Microbiology and Infection Control, Leiden University Medical Center, Leiden, The Netherlands
University Medical Center Groningen (NL)
Corresponding author: Zhang, Jianhua
ORCID: Zhang, Jianhua
Snelders, Eveline
Zwaan, Bas J.
Schoustra, Sijmen E.
Meis, Jacques F.
Hagen, Ferry
Kampinga, Greetje A.
Zoll, Jan
Melchers, Willem J. G.
Verweij, Paul E.
Debets, Alfons J. M.
Venue: mBio
Publisher: American Society for Microbiology
Published: 2017-07-05
Volume: 8
Issue: 3
ISSN: 2150-7511 (ISSN-L)
2161-2129
DOI: 10.1128/mbio.00791-17
PMC: PMC5487732
OpenAlex: W2729257211
Cited by: 129
References: 68
Citations by year: 2026: 5 · 2025: 13 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 26 · 2020: 20 · 2019: 21 · 2018: 9 · 2017: 7
FWCI: 12.00
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
journals.asm.org/non-commercial-tdm-license (tdm)
Locations: mBio (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Pure Amsterdam UMC (publishedVersion, other-oa)
University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
Radboud Repository (Radboud University) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Data Archiving and Networked Services (DANS) (submittedVersion)
Leiden Repository (Leiden University) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Socio-Environmental Systems Modeling (submittedVersion, cc-by)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
Radboud Repository (Radboud University) (submittedVersion, other-oa)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders: China Scholarship Council (CSC No.2011677021)
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: azole resistance, sexual reproduction, composting, unequal crossover, tandem repeats, genetic diversity, clinical isolates, heat shock, meiosis, molecular epidemiology
MeSH terms: Composting, Antifungal Agents, Aspergillosis, Aspergillus fumigatus, Azoles, Crosses, Genetic, Genotype, Humans, Mutation, Netherlands, Soil Microbiology, Drug Resistance, Fungal

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A Novel Environmental Azole Resistance Mutation in Aspergillus fumigatus and a Possible Role of Sexual Reproduction in Its Emergence

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