AtrR Is an Essential Determinant of Azole Resistance in Aspergillus fumigatus
Open accessAbstract
Aspergillus fumigatus is the major filamentous fungal pathogen in humans. Infections associated with A. fumigatus are often treated with azole drugs, but resistance to these antifungal agents is increasing. Mortality from aspergillosis associated with azole-resistant fungi is extremely high. Previous work has identified transcriptional control of the azole drug target-encoding gene cyp51A as an important contributor to resistance in A. fumigatus . Here, we demonstrate that the transcription factor AtrR binds to a region in the cyp51A promoter that is associated with alleles of this gene conferring clinically important azole resistance. Using high-throughput genomic technologies, we also uncover a large suite of target genes controlled by AtrR. These data indicate that AtrR coordinately regulates many different processes involved in drug resistance, metabolism, and virulence. Our new understanding of AtrR function provides important new insight into the pathogenesis of A. fumigatus .
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA.
“Additional regulators of cyp51A expression that contribute to azole resistance in A. fumigatus include the fungal-specific transcription factors AtrR and SltA30–32.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [31]
In A. fumigatus, the fungal-specific Zn2-Cys6 type transcription factor AtrR plays a pivotal role in regulating expression of cyp51A.
“Additionally, in A. fumigatus, the fungal-specific Zn2-Cys6 type transcription factor AtrR plays a pivotal role in regulating the expression of cyp51A30,31.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [31]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
HISAT: a fast spliced aligner with low memory requirements
Kim, D., Langmead, B., & Salzberg, S. L. (2015) · Nature Methods · doi:10.1038/nmeth.3317 · Cited by 24,112 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
MEME SUITE: tools for motif discovery and searching
Bailey, T. L., Boden, M., Buske, F. A., Frith, M., Grant, C. E., Clementi, L., Ren, J., Li, W. W., & Noble, W. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp335 · Cited by 10,648 · see citing works
Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown
Pertea, M., Kim, D., Pertea, G. M., Leek, J. T., & Salzberg, S. L. (2016) · Nature Protocols · doi:10.1038/nprot.2016.095 · Cited by 6,708 · see citing works
MEME-ChIP: motif analysis of large DNA datasets
Machanick, P., & Bailey, T. L. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr189 · Cited by 1,815 · see citing works
Identifying ChIP-seq enrichment using MACS
Feng, J., Liu, T., Qin, B., Zhang, Y., & Liu, X. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.101 · Cited by 1,805 · see citing works
ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data
Zhu, L., Gazin, C., Lawson, N., Pagès, H., Lin, S. M., Lapointe, D. S., & Green, M. R. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-237 · Cited by 1,144 · see citing works
Meiotic and Mitotic Recombination in Aspergillus and Its Chromosomal Aberrations
Käfer, E. (1977) · Advances in genetics · doi:10.1016/s0065-2660(08)60245-x · Cited by 740 · see citing works
Emergence of Azole Resistance in Aspergillus fumigatus and Spread of a Single Resistance Mechanism
Snelders, E., van der Lee, H. A. L., Kuijpers, J., Rijs, A. J. M. M., Varga, J., Samson, R. A., Mellado, E., Donders, A. R. T., Melchers, W. J. G., & Verweij, P. E. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050219 · Cited by 726 · see citing works
Schrettl, M., Bignell, E., Kragl, C., Joechl, C., Rogers, T., Arst, H. N., Haynes, K., & Haas, H. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041242 · Cited by 493 · see citing works
Willger, S. D., Puttikamonkul, S., Kim, K.-H., Burritt, J. B., Grahl, N., Metzler, L. J., Barbuch, R., Bard, M., Lawrence, C. B., & Cramer, R. A. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.1000200 · Cited by 345 · see citing works
van der Linden, J. W. M., Camps, S. M. T., Kampinga, G. A., Arends, J. P. A., Debets-Ossenkopp, Y. J., Haas, P. J. A., Rijnders, B. J. A., Kuijper, E. J., van Tiel, F. H., Varga, J., et al. (2013) · Clinical Infectious Diseases · doi:10.1093/cid/cit320 · Cited by 342 · see citing works
Hahn, S., & Young, E. T. (2011) · Genetics · doi:10.1534/genetics.111.127019 · Cited by 341 · see citing works
Fraczek, M. G., Bromley, M., Buied, A., Moore, C. B., Rajendran, R., Rautemaa‐Richardson, R., Ramage, G., Denning, D. W., & Bowyer, P. (2013) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkt075 · Cited by 313 · see citing works
Ubiquitin and Proteasomes in Transcription
Geng, F.-Q., Wenzel, S., & Tansey, W. (2012) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052110-120012 · Cited by 302 · see citing works
FungiFun2: a comprehensive online resource for systematic analysis of gene lists from fungal species
Priebe, S., Kreisel, C., Horn, F., Guthke, R., & Linde, J. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu627 · Cited by 224 · see citing works
Camps, S. M. T., Dutilh, B. E., Arendrup, M. C., Rijs, A. J. M. M., Snelders, E., Huynen, M. A., Verweij, P. E., & Melchers, W. J. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050034 · Cited by 208 · see citing works
Chung, D., Barker, B. M., Carey, C. C., Merriman, B., Werner, E. R., Lechner, B. E., Dhingra, S., Cheng, C., Xu, W., Blosser, S. J., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004487 · Cited by 193 · see citing works
Blatzer, M., Barker, B. M., Willger, S. D., Beckmann, N., Blosser, S. J., Cornish, E. J., Mazurie, A., Grahl, N., Haas, H., & Cramer, R. A. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002374 · Cited by 175 · see citing works
Hagiwara, D., Miura, D., Shimizu, K., Paul, S., Ohba, A., Gonoi, T., Watanabe, A., Kamei, K., Shintani, T., Moye-Rowley, W. S., et al. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006096 · Cited by 156 · see citing works
Self-citationInhibiting fungal multidrug resistance by disrupting an activator–Mediator interaction
Nishikawa, J. L., Boeszoermenyi, A., Vale-Silva, L. A., Torelli, R., Posteraro, B., Sohn, Y.-J., Ji, F., Gelev, V., Sanglard, D., Sanguinetti, M., et al. (2016) · Nature · doi:10.1038/nature16963 · Cited by 146 · see citing works
Alvarez-Moreno, C., Lavergne, R.-A., Hagen, F., Morio, F., Meis, J. F., & Le Pape, P. (2017) · Scientific Reports · doi:10.1038/srep45631 · Cited by 141 · see citing works
Gsaller, F., Hortschansky, P., Beattie, S. R., Klammer, V., Tuppatsch, K., Lechner, B. E., Rietzschel, N., Werner, E. R., Vogan, A. A., Chung, D., et al. (2014) · The EMBO Journal · doi:10.15252/embj.201489468 · Cited by 134 · see citing works
Gsaller, F., Hortschansky, P., Furukawa, T., Carr, P. D., Rash, B. M., Capilla, J., Müller, C., Bracher, F., Bowyer, P., Haas, H., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005775 · Cited by 134 · see citing works
The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus
Furukawa, T., van Rhijn, N., Fraczek, M. G., Gsaller, F., Davies, E. A., Carr, P. D., Gago, S., Fortune‐Grant, R., Rahman, S., Gilsenan, J. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14191-1 · Cited by 133 · see citing works
Self-citationZhang, 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., et al. (2017) · mBio · doi:10.1128/mbio.00791-17 · Cited by 129 · see citing works
Gibbons, J. G., Beauvais, A., Beau, R., McGary, K. L., Latgé, J., & Rokas, A. (2011) · Eukaryotic Cell · doi:10.1128/ec.05102-11 · Cited by 115 · see citing works
Dhingra, S., & Cramer, R. A. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00092 · Cited by 114 · see citing works
Snelders, E., Karawajczyk, A., Verhoeven, R. J. A., Venselaar, H., Schaftenaar, G., Verweij, P. E., & Melchers, W. J. G. (2011) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2011.08.002 · Cited by 113 · see citing works
Paul, S. K., Diekema, D. J., & Moye-Rowley, S. (2013) · Eukaryotic Cell · doi:10.1128/ec.00171-13 · Cited by 91 · see citing works
Self-citationRegulation of the CgPdr1 Transcription Factor from the Pathogen Candida glabrata
Paul, S., Schmidt, J. A., & Moye-Rowley, W. S. (2011) · Eukaryotic Cell · doi:10.1128/ec.00277-10 · Cited by 78 · see citing works
Self-citationChiang, L. Y., Sheppard, D. C., Gravelat, F. N., Patterson, T. F., & Filler, S. G. (2008) · Infection and Immunity · doi:10.1128/iai.01510-07 · Cited by 76 · see citing works
Self-citationPaul, S. K., Diekema, D. J., & Moye-Rowley, S. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02748-16 · Cited by 69 · see citing works
Self-citationKato, M. (2005) · Bioscience Biotechnology and Biochemistry · doi:10.1271/bbb.69.663 · Cited by 59 · see citing works
Azole resistance surveillance inAspergillus fumigatus: beneficial or biased?
Verweij, P. E., Lestrade, P. P. A., Melchers, W. J. G., & Meis, J. F. G. M. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkw259 · Cited by 59 · see citing works
Vu, B. G., Thomas, G. H., & Moye-Rowley, W. S. (2019) · mBio · doi:10.1128/mbio.00934-19 · Cited by 59 · see citing works
Self-citationLiu, M., Zheng, N., Li, D., Zheng, H., Zhang, L., Ge, H., & Liu, W. (2016) · Medical Mycology · doi:10.1093/mmy/myv102 · Cited by 48 · see citing works
Qiao, J., Kontoyiannis, D. P., Calderone, R., Li, D., Ma, Y., Wan, Z., Li, R., & Liu, W. Y. (2008) · Medical Mycology · doi:10.1080/13693780802054215 · Cited by 46 · see citing works
Paul, S., Bair, T. B., & Moye-Rowley, W. S. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03921-14 · Cited by 45 · see citing works
Self-citationGravelat, F. N., Askew, D. S., & Sheppard, D. C. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-539-8_8 · Cited by 39 · see citing works
Analysis of Promoter Function in Aspergillus fumigatus
Paul, S. K., Klutts, J. S., & Moye-Rowley, S. (2012) · Eukaryotic Cell · doi:10.1128/ec.00174-12 · Cited by 28 · see citing works
Self-citationStructural basis of HapEP88L-linked antifungal triazole resistance in Aspergillus fumigatus
Hortschansky, P., Misslinger, M., Mörl, J., Gsaller, F., Bromley, M., Brakhage, A. A., Groll, M., Haas, H., & Huber, E. M. (2020) · Life Science Alliance · doi:10.26508/lsa.202000729 · Cited by 27 · see citing works
James, J. E., Lamping, E., Santhanam, J., Milne, T. J., Razak, M. F. A., Zakaria, L., & Cannon, R. D. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00272 · Cited by 20 · see citing works
Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity
Liu, H., Xu, W., Solis, N. V., Woolford, C. A., Mitchell, A. P., & Filler, S. G. (2018) · Virulence · doi:10.1080/21505594.2018.1482182 · Cited by 19 · see citing works
Self-citationNash, A., & Rhodes, J. L. (2017) · Medical Mycology · doi:10.1093/mmy/myx056 · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tackling the emerging threat of antifungal resistance to human health
Fisher, M. C., Alastruey-Izquierdo, A., Berman, J., Bicanic, T., Bignell, E. M., Bowyer, P., Bromley, M., Brüggemann, R., Garber, G., Cornely, O. A., et al. (2022) · Nature Reviews Microbiology · doi:10.1038/s41579-022-00720-1 · Cited by 1,179 · see citing works
The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin
Hoenigl, M., Sprute, R., Egger, M., Arastehfar, A., Cornely, O. A., Krause, R., Lass-Flörl, C., Prattes, J., Spec, A., Thompson, G. R., et al. (2021) · Drugs · doi:10.1007/s40265-021-01611-0 · Cited by 467 · see citing works
Molecular mechanisms governing antifungal drug resistance
Lee, Y., Robbins, N., & Cowen, L. E. (2023) · npj Antimicrobials and Resistance · doi:10.1038/s44259-023-00007-2 · Cited by 304 · see citing works
Vu, B. G., Thomas, G. H., & Moye-Rowley, W. S. (2019) · mBio · doi:10.1128/mbio.00934-19 · Cited by 59 · see citing works
Self-citationDu, W., Zhai, P., Wang, T., Bromley, M. J., Zhang, Y., & Lu, L. (2021) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01839-20 · Cited by 46 · see citing works
Vu, B. G., Stamnes, M. A., Li, Y., Rogers, P. D., & Moye-Rowley, W. S. (2021) · PLOS Genetics · doi:10.1371/journal.pgen.1009582 · Cited by 39 · see citing works
Self-citationLinkage between genes involved in azole resistance and ergosterol biosynthesis
Moye-Rowley, W. S. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008819 · Cited by 29 · see citing works
Self-citation
- Authors
- Paul, S., Stamnes, M., Thomas, G. H., Liu, H., Hagiwara, D., Gomi, K., Filler, S. G., & Moye-Rowley, W. S.
- Affiliations
- University of Iowa (US)
- University of California, Los Angeles (US)
- University of Tsukuba (JP)
- Tohoku University (JP)
- Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2019-04-30
- Volume
- 10
- Issue
- 2
- Pages
- e02563-18
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC6414702
- OpenAlex
- W2921606435
- Cited by
- 91
- References
- 46
- Citations by year
- 2026: 16 · 2025: 10 · 2024: 9 · 2023: 16 · 2022: 11 · 2021: 19 · 2020: 7 · 2019: 3
- FWCI
- 7.67
- 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)
- Institutional Repositories DataBase (IRDB) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Terrestrial Environment Research Center (University of Tsukuba) (submittedVersion)
- Funders
- HHS | National Institutes of Health (GM49825, AI113748, AI124566)
- 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, Aspergillus fumigatus, cyp51A, transcription factors, promoter binding, transcriptional regulation, therapeutic target, aspergillosis, antifungal resistance, target genes, virulence, metabolism
- MeSH terms
- Antifungal Agents, Aspergillus fumigatus, Azoles, DNA, Fungal, Fungal Proteins, Mutation, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Gene Expression Regulation, Fungal, Gene Deletion, Sequence Analysis, DNA, Regulon, Gene Expression Profiling, Electrophoretic Mobility Shift Assay, Drug Resistance, Fungal, Chromatin Immunoprecipitation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
