CDR4 is the major contributor to azole resistance among four Pdr5p-like ABC transporters in Neurospora crassa.
Abstract
Pdr5p-like ABC transporters play a significant role in azole resistance in Saccharomyces cerevisiae and Candida spp. Most of filamentous fungal species have multiple Pdr5p homologues. In this study, phylogenic analysis identified that filamentous fungi have at least two phylogenically distant groups of Pdr5p homologues. One contains PMR1-like Pdr5p homologues while the other contains both AtrF-like and AtrB-like Pdr5p homologues. Neurospora crassa has a total of four genes encoding Pdr5p homologues including CDR4 (PMR1-like), ATRB (AtrB-like), and ATRF (AtrF-like) and ATRF-2 (AtrF-like). By analyzing the susceptibilities of their knockout mutants to azole drugs including ketoconazole, fluconazole, and itraconazole, we found that deletion of cdr4 increased the susceptibility to antifungal azoles. In contrast, neither single-gene nor triple-gene deletion of atrb, atrf, and atrf-2 could not alter the susceptibility to azoles. In addition, cdr4, but not other Pdr5p homologue-coding genes, responded transcriptionally to ketoconazole stress. Together with the previous findings in other fungal species, these results suggest that the PMR1-like but not the AtrF-like or AtrB-like Pdr5p homologues play a key role in antifungal azole resistance in filamentous fungi.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Deletion of cdr4 in N. crassa resulted in hypersensitivity to azoles.
“Deletion of cdr4 in N. crassa resulted in hypersensitive to azoles (Zhang et al., 2012).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Zhang et al., 2012
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
PAUP^* : Phylogenetic Analysis Using Parsimony (and other methods) 4.0b8
Swofford, D. L. (2001) · Cited by 12,789 · see citing works
PAUP * [Phylogenetic Analysis Using Parsimony (and Other Methods)]
Cummings, M. P. (2004) · Dictionary of Bioinformatics and Computational Biology · doi:10.1002/0471650129.dob0522 · Cited by 5,229 · see citing works
PAUP (phylogenetic analysis using parsimony)
(2008) · Springer eBooks · doi:10.1007/978-1-4020-6754-9_12413 · Cited by 4,424 · see citing works
Sanglard, D., Kuchler, K., Ischer, F., Pagani, J. L., Monod, M., & Bille, J. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.11.2378 · Cited by 815 · see citing works
White, T. C. (1997) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.41.7.1482 · Cited by 612 · see citing works
Sanglard, D., Ischer, F., Monod, M., & Bille, J. (1997) · Microbiology · doi:10.1099/00221287-143-2-405 · Cited by 587 · see citing works
Prasad, R., De Wergifosse, P., Goffeau, A., & Balzi, E. (1995) · Current Genetics · doi:10.1007/bf00352101 · Cited by 486 · see citing works
Kołaczkowski, M., Michel, V. D. R., Cybularz-Kolaczkowska, A., Soumillion, J., Konings, W. N., & Goffeau, A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.49.31543 · Cited by 323 · see citing works
Liu, T. T., Lee, R. E. B., Barker, K. S., Lee, R. E., Wei, L., Homayouni, R., & Rogers, P. D. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.6.2226-2236.2005 · Cited by 313 · see citing works
An ATP‐driven efflux pump is a novel pathogenicity factor in rice blast disease
Urban, M., Bhargava, T., & Hamer, J. E. (1999) · The EMBO Journal · doi:10.1093/emboj/18.3.512 · Cited by 269 · see citing works
Schoonbeek, H., Sorbo, G. D., & Waard, M. A. D. (2001) · Molecular Plant-Microbe Interactions · doi:10.1094/mpmi.2001.14.4.562 · Cited by 224 · see citing works
Agarwal, A. K., Rogers, P. D., Baerson, S. R., Jacob, M. R., Barker, K. S., Cleary, J. D., Walker, L. A., Nagle, D. G., & Clark, A. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306291200 · Cited by 204 · see citing works
Slaven, J. W., Anderson, M. J., Sanglard, D., Dixon, G. K., Bille, J., Roberts, I. S., & Denning, D. W. (2002) · Fungal Genetics and Biology · doi:10.1016/s1087-1845(02)00016-6 · Cited by 202 · see citing works
Nakaune, R., Adachi, K., Nawata, O., Tomiyama, M., AKUTSU, K., & Hibi, T. (1998) · Applied and Environmental Microbiology · doi:10.1128/aem.64.10.3983-3988.1998 · Cited by 197 · see citing works
Cloning by gene amplification of two loci conferring multiple drug resistance in Saccharomyces.
Leppert, G. S., McDevitt, R. E., Falco, S. C., Dyk, T. K. V., Ficke, M. B., & Golin, J. E. (1990) · Genetics · doi:10.1093/genetics/125.1.13 · Cited by 183 · see citing works
Transcriptome analysis of Aspergillus fumigatus exposed to voriconazole
Ferreira, M. E. D. S., Malavazi, I., Savoldi, M., Brakhage, A. A., Goldman, M. H. S., Kim, H. S., Nierman, W. C., & Goldman, G. H. (2006) · Current Genetics · doi:10.1007/s00294-006-0073-2 · Cited by 159 · see citing works
Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters
Sorbo, G. D., Andrade, A. C., van Nistelrooy, J. G. M., van Kan, J. A. L., Balzi, E., & Waard, M. A. D. (1997) · Molecular and General Genetics MGG · doi:10.1007/s004380050434 · Cited by 137 · see citing works
Andrade, A. C., Sorbo, G. D., van Nistelrooy, J. G. M., & Waard, M. A. D. (2000) · Microbiology · doi:10.1099/00221287-146-8-1987 · Cited by 132 · see citing works
Vermeulen, T. M. M., Schoonbeek, H., & Waard, M. A. D. (2001) · Pest Management Science · doi:10.1002/ps.309 · Cited by 108 · see citing works
Hayashi, K., Schoonbeek, H., & Waard, M. A. D. (2002) · Pesticide Biochemistry and Physiology · doi:10.1016/s0048-3575(02)00015-9 · Cited by 99 · see citing works
Schuetzer‐Muehlbauer, M. (2003) · International Journal of Antimicrobial Agents · doi:10.1016/s0924-8579(03)00213-9 · Cited by 97 · see citing works
Nakaune, R., Hamamoto, H., Imada, J., AKUTSU, K., & Hibi, T. (2002) · Molecular Genetics and Genomics · doi:10.1007/s00438-002-0649-6 · Cited by 97 · see citing works
Zwiers, L. H., Stergiopoulos, I., Gielkens, M. M. C., Goodall, S. D., & Waard, M. A. D. (2003) · Molecular Genetics and Genomics · doi:10.1007/s00438-003-0855-x · Cited by 75 · see citing works
Regulated overexpression of CDR1 in Candida albicans confers multidrug resistance
Niimi, M., Niimi, K., Takano, Y., Holmes, A. R., Fischer, F. J., Uehara, Y., & Cannon, R. D. (2004) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkh456 · Cited by 69 · see citing works
Zwiers, L. H., & Waard, M. A. D. (2000) · Fungal Genetics and Biology · doi:10.1006/fgbi.2000.1209 · Cited by 56 · see citing works
Lee, Y.-J., Yamamoto, K., Hamamoto, H., Nakaune, R., & Hibi, T. (2004) · Pesticide Biochemistry and Physiology · doi:10.1016/j.pestbp.2004.07.007 · Cited by 45 · see citing works
Role of a Fusarium culmorum ABC transporter (FcABC1) during infection of wheat and barley
Skov, J., Lemmens, M., & Giese, H. (2004) · Physiological and Molecular Plant Pathology · doi:10.1016/j.pmpp.2004.09.005 · Cited by 38 · see citing works
Krishnamurthy, S., Chatterjee, U., Gupta, V., Prasad, R., Das, P. K., Snehlata, P., Hasnain, S. E., & Prasad, R. (1998) · Yeast · doi:10.1002/(sici)1097-0061(19980430)14:6 · Cited by 38 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Genomes of Three Uneven Siblings: Footprints of the Lifestyles of Three Trichoderma Species
Schmoll, M., Dattenböck, C., Carreras-Villaseñor, N., Mendoza‐Mendoza, A., Tisch, D., Alemán-Duarte, M. I., Baker, S., Brown, C. M., Cervantes-Badillo, M. G., Cetz-Chel, J. E., et al. (2016) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00040-15 · Cited by 190 · 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
Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles
Hu, C., Zhou, M., Wang, W., Sun, X., Yarden, O., & Li, S. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00009 · Cited by 114 · see citing works
Self-citationYan, J. Y., Zhao, W. S., Chen, Z., Xing, Q. K., Zhang, W., Chethana, K. W. T., Xue, M. F., Xu, J. P., Phillips, A. J. L., Wang, Y., et al. (2017) · DNA Research · doi:10.1093/dnares/dsx040 · Cited by 108 · see citing works
Molecular tools for functional genomics in filamentous fungi: Recent advances and new strategies
Jiang, D., Zhu, W., Wang, Y., Sun, C., Zhang, K., & Yang, J. (2013) · Biotechnology Advances · doi:10.1016/j.biotechadv.2013.08.005 · Cited by 107 · see citing works
An update on ABC transporters of filamentous fungi – from physiological substrates to xenobiotics
Víglaš, J., & Olejníková, P. (2021) · Microbiological Research · doi:10.1016/j.micres.2020.126684 · Cited by 91 · see citing works
Coordinated and Distinct Functions of Velvet Proteins in Fusarium verticillioides
Lan, N., Zhang, H., Hu, C., Wang, W., Calvo, A. M., Harris, S. D., Chen, S., & Li, S. (2014) · Eukaryotic Cell · doi:10.1128/ec.00022-14 · Cited by 39 · see citing works
Self-citationEsquivel, B. D., Rybak, J. M., Barker, K. S., Fortwendel, J. R., Rogers, P. D., & White, T. C. (2020) · mBio · doi:10.1128/mbio.00338-20 · Cited by 35 · see citing works
Yu, C., Diao, Y., Lü, Q., Zhao, J., Cui, S., Xiong, X., Lu, A., Zhang, X., & Liu, H. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.800981 · Cited by 34 · see citing works
Self-citationTranscription factor CCG-8 as a new regulator in the adaptation to antifungal azole stress.
Sun, X., Wang, K., Yu, X., Liu, J., Zhang, H., Zhou, F., Xie, B., & Li, S. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02244-13 · Cited by 30 · see citing works
Self-citationThe Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles
Gu, X., Xue, W., Yin, Y.-J., Liu, H.-W., Li, S.-J., & Sun, X.-Y. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.01571 · Cited by 26 · see citing works
Self-citationThe Oxygenase CAO-1 of Neurospora crassa Is a Resveratrol Cleavage Enzyme
Díaz‐Sánchez, V., Estrada, A. F., Limón, M. C., Al‐Babili, S., & Ávalos, J. (2013) · Eukaryotic Cell · doi:10.1128/ec.00084-13 · Cited by 24 · see citing works
Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress
Wang, K., Zhang, Z., Chen, X., Sun, X., Jin, C., Liu, H., & Li, S. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00542-15 · Cited by 21 · see citing works
Self-citationDe-repression of CSP-1 activates adaptive responses to antifungal azoles.
Chen, X., Xue, W., Zhou, J., Zhang, Z., Wei, S., Liu, X., Sun, X., Wang, W., & Li, S. (2016) · Scientific Reports · doi:10.1038/srep19447 · Cited by 20 · see citing works
Self-citationGonçalves, A. P., Hall, C., Kowbel, D., Glass, N. L., & Videira, A. (2014) · G3 Genes Genomes Genetics · doi:10.1534/g3.114.011312 · Cited by 17 · see citing works
Yin, Y., Zhang, H., Zhang, Y., Hu, C., Sun, X., Liu, W. Y., & Li, S. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01316-20 · Cited by 17 · see citing works
Self-citationZhu, J., Yu, X., Xie, B., Gu, X., Zhang, Z., & Li, S. (2013) · Fungal Biology · doi:10.1016/j.funbio.2013.04.006 · Cited by 12 · see citing works
Self-citationXue, W., Yin, Y., Ismail, F., Hu, C., Zhou, M., Cao, X., Li, S., & Sun, X. (2019) · Current Genetics · doi:10.1007/s00294-018-0924-7 · Cited by 12 · see citing works
Self-citationZhao, Y., Sun, H., Li, J., Ju, C., & Huang, J. (2022) · Biology · doi:10.3390/biology11020326 · Cited by 10 · see citing works
Piombo, E., Tzelepis, G. D., Ruus, A. G., Rafiei, V., Jensen, D. F., Karlsson, M., & Dubey, M. K. (2024) · Microbiological Research · doi:10.1016/j.micres.2024.127922 · Cited by 9 · see citing works
Kuan, C. S., Ng, K. P., Yew, S. M., Meleh, H. U., Seow, H. F., How, K. N., Yeo, S. K., Jee, J. M., Tan, Y.-C., Yee, W.-Y., et al. (2023) · Brazilian Journal of Microbiology · doi:10.1007/s42770-023-01032-z · Cited by 8 · see citing works
Experimental Evolution of Multidrug Resistance in Neurospora crassa under Antifungal Azole Stress
Zhou, M., Hu, C., Yin, Y., Wang, J., Ye, S., Yu, Y., Sun, X., & Li, S. (2022) · Journal of Fungi · doi:10.3390/jof8020198 · Cited by 6 · see citing works
Self-citationGonçalves, A. P., Silva, N. A., Oliveíra, C., Kowbel, D., Glass, N. L., Kijjoa, A., Palmeira, A., Sousa, E., Pinto, M. M. M., & Videira, A. (2015) · Genomics Data · doi:10.1016/j.gdata.2015.02.001 · Cited by 6 · see citing works
Ding, Y., Chai, Y., Li, S., Wu, Z., Zou, M., Zhang, L., Kusum, R., & Qian, W. (2025) · Journal of Integrative Agriculture · doi:10.1016/j.jia.2025.02.014 · Cited by 6 · see citing works
Self-citationHu, C., Zhou, M., Cao, X., Xue, W., Zhang, Z., Li, S., & Sun, X. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.00127-22 · Cited by 4 · see citing works
Self-citationKumari, D., Kumar, M., Gaur, N. A., Duhan, L., Павловна, С. Н., Manoharlal, R., & Pasrija, R. (2025) · Journal of Cell Science · doi:10.1242/jcs.263558 · Cited by 3 · see citing works
Zhao, R., Suo, X., Meng, X., Wang, Y., Dai, P., Hu, T., Cao, K., Wang, S., & Li, B. (2024) · Journal of Fungi · doi:10.3390/jof10120883 · Cited by 2 · see citing works
Abrantes, P. M. D. S., Fisher, R., Bouic, P. J., McArthur, C. P., Fielding, B. C., Africa, C. W. J., & Synexa Life Sciences, P. B. 3. (2021) · AIMS Microbiology · doi:10.3934/microbiol.2021020 · Cited by 2 · see citing works
Kuan, C. S., Ng, K. P., Yew, S. M., Meleh, H. U., Seow, H. F., How, K. N., Yeo, S. K., Jee, J. M., Tan, Y.-C., Yee, W.-Y., et al. (2020) · doi:10.21203/rs.3.rs-96876/v1 · Cited by 2 · see citing works
Polley, S. K., & Ghosh, S. K. (2025) · Gene Reports · doi:10.1016/j.genrep.2025.102135 · Cited by 1 · see citing works
Ghosh, S. K., & Polley, S. K. (2025) · Vegetos · doi:10.1007/s42535-025-01518-1 · Cited by 1 · see citing works
Piombo, E., Tzelepis, G. D., Ruus, A. G., Rafiei, V., Jensen, D. F., Karlsson, M., & Dubey, M. K. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.26.582079
- Authors
- Zhang, Y., Zhang, Z., Zhang, X., Zhang, H., Sun, X., Hu, C., & Li, S.
- Affiliations
- Chinese Academy of Sciences (CN)
- Corresponding author
- Li, Shaojie
- Venue
- Fungal Biology
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 116
- Issue
- 7
- Pages
- 848-854
- ISSN
- 1878-6146 (ISSN-L)
- OpenAlex
- W2040555515
- Cited by
- 32
- References
- 29
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 4
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Fungal Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- azole resistance, Neurospora crassa, ketoconazole, fluconazole, itraconazole, antifungal susceptibility, knockout mutants, filamentous fungi, phylogenetic analysis
- MeSH terms
- Antifungal Agents, Fungal Proteins, Ketoconazole, Microbial Sensitivity Tests, Neurospora crassa, Phylogeny, Fluconazole, Sequence Homology, Amino Acid, Itraconazole, ATP-Binding Cassette Transporters, Drug Resistance, Fungal, Gene Knockout Techniques
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