Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata
Open accessAbstract
The frequent emergence of azole resistance among Candida glabrata strains contributes to increase the incidence of infections caused by this species. Whole-genome sequencing of a fluconazole and voriconazole-resistant clinical isolate (FFUL887) and subsequent comparison with the genome of the susceptible strain CBS138 revealed prominent differences in several genes documented to promote azole resistance in C. glabrata. Among these was the transcriptional regulator CgPdr1. The CgPdr1 FFUL887 allele included a K274Q modification not documented in other azole-resistant strains. Transcriptomic profiling evidenced the upregulation of 92 documented targets of CgPdr1 in the FFUL887 strain, supporting the idea that the K274Q substitution originates a CgPdr1 gain-of-function mutant. The expression of CgPDR1K274Q in the FFUL887 background sensitised the cells against high concentrations of organic acids at a low pH (4.5), but had no detectable effect in tolerance towards other environmental stressors. Comparison of the genome of FFUL887 and CBS138 also revealed prominent differences in the sequence of adhesin-encoding genes, while comparison of the transcriptome of the two strains showed a significant remodelling of the expression of genes involved in metabolism of carbohydrates, nitrogen and sulphur in the FFUL887 strain; these responses likely reflecting adaptive responses evolved by the clinical strain during colonisation of the host.
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?
At least 78 genes have been suggested to be implicated in C. glabrata resistance to fluconazole and voriconazole.
“However, there may still be alternative routes to the acquisition of resistance in C. glabrata, as there have been at least 78 genes suggested to be implicated in C. glabrata resistance to fluconazole and voriconazole [104].”
From Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens (2018) · cites this paper as [104]
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
Dujon, B., Sherman, D., Fischer, G., Durrens, P., Casaregola, S., Lafontaine, I., de Montigny, J., Marck, C., Neuvéglise, C., Talla, E., et al. (2004) · Nature · doi:10.1038/nature02579 · Cited by 1,623 · see citing works
Fidel, P. L., Vazquez, J. A., & Sobel, J. D. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.1.80 · Cited by 953 · see citing works
Xanthomonas citri MinC Oscillates from Pole to Pole to Ensure Proper Cell Division and Shape
Lorenzoni, A. S. G., Dantas, G. C., Bergsma, T., Ferreira, H., & Scheffers, D. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01352 · Cited by 727 · see citing works
Pfaller, M. A., Diekema, D. J., Gibbs, D. L., Newell, V. A., Ellis, D., Tullio, V., Rodloff, A., Fu, W., & Ling, T. A. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.02117-09 · Cited by 718 · see citing works
Sanglard, D., Ischer, F., Calabrese, D., Majcherczyk, P. A., & Bille, J. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.11.2753 · Cited by 337 · see citing works
Garcia-Effron, G., Lee, S., Park, S., Cleary, J. D., & Perlin, D. S. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00443-09 · Cited by 323 · see citing works
Sanguinetti, M., Posteraro, B., Fiori, B., Ranno, S., Torelli, R., & Fadda, G. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.2.668-679.2005 · Cited by 319 · see citing works
Ferrari, S., Ischer, F., Calabrese, D., Posteraro, B., Sanguinetti, M., Fadda, G., Rohde, B., Bauser, C., Bader, O., & Sanglard, D. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000268 · Cited by 295 · see citing works
Vermitsky, J.-P., & Edlind, T. D. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.10.3773-3781.2004 · Cited by 285 · see citing works
Healey, K. R., Zhao, Y., Perez, W. B., Lockhart, S. R., Sobel, J. D., Farmakiotis, D., Kontoyiannis, D. P., Sanglard, D., Taj-Aldeen, S. J., Alexander, B. D., et al. (2016) · Nature Communications · doi:10.1038/ncomms11128 · Cited by 276 · see citing works
Pfaller, M. A., Messer, S. A., Woosley, L. N., Jones, R. N., & Castanheira, M. (2013) · Journal of Clinical Microbiology · doi:10.1128/jcm.00308-13 · Cited by 237 · see citing works
Tsai, H.-F., Krol, A. A., Sarti, K. E., & Bennett, J. E. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.50.4.1384-1392.2006 · Cited by 237 · see citing works
Vermitsky, J., Earhart, K. D., Smith, W. L., Homayouni, R., Edlind, T. D., & Rogers, P. D. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05235.x · Cited by 233 · see citing works
Treatment of epidemic and pandemic influenza with neuraminidase and M2 proton channel inhibitors
OXFORD, J. S., Bossuyt, S., Balasingam, S., Mann, A., Novelli, P., & Lambkin‐Williams, R. (2003) · Clinical Microbiology and Infection · doi:10.1046/j.1469-0691.2003.00564.x · Cited by 231 · see citing works
Schwarzmüller, T., Ma, B., Hiller, E., Istel, F., Tscherner, M., Brunke, S., Ames, L., Firon, A., Green, B., Cabral, V., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004211 · Cited by 191 · see citing works
Torelli, R., Posteraro, B., Ferrari, S., La Sorda, M., Fadda, G., Sanglard, D., & Sanguinetti, M. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06143.x · Cited by 141 · see citing works
Pfaller, M. A., Andes, D., Arendrup, M. C., Diekema, D. J., Espinel-Ingroff, A., Alexander, B. D., Brown, S. D., Chaturvedi, V., Fowler, C. L., Ghannoum, M. A., et al. (2011) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2011.03.002 · Cited by 130 · see citing works
MFS multidrug transporters in pathogenic fungi: do they have real clinical impact?
Costa, C., Dias, P. J., Sá‐Correia, I., & Teixeira, M. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00197 · Cited by 115 · see citing works
Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata
Ferrari, S., Sanguinetti, M., Torelli, R., Posteraro, B., & Sanglard, D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017589 · Cited by 110 · see citing works
Ueno, K., Matsumoto, Y., Uno, J., Sasamoto, K., Sekimizu, K., Kinjo, Y., & Chibana, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024759 · Cited by 109 · see citing works
Self-citationBorst, A., Raimer, M. T., Warnock, D. W., Morrison, C. J., & Arthington, B. A. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.2.783-787.2005 · Cited by 107 · see citing works
Genomewide Expression Profile Analysis of the Candida glabrata Pdr1 Regulon
Caudle, K. E., Barker, K. S., Wiederhold, N. P., Xu, L., Homayouni, R., & Rogers, P. D. (2010) · Eukaryotic Cell · doi:10.1128/ec.00073-10 · Cited by 92 · see citing works
Drug resistance mechanisms and their regulation in non- albicans Candida species
Kołaczkowska, A., & Kołaczkowski, M. (2016) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv445 · Cited by 88 · see citing works
Childers, D. S., Raziunaite, I., Mol Avelar, G., Mackie, J., Budge, S., Stead, D., Gow, N. A. R., Lenardon, M. D., Ballou, E. R., MacCallum, D. M., et al. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005566 · Cited by 81 · see citing works
Tsai, H.-F., Sammons, L. R., Zhang, X., Suffis, S. D., Su, Q., Myers, T. G., Marr, K. A., & Bennett, J. E. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00535-10 · Cited by 80 · see citing works
Regulation 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
Transcriptional Response of Candida parapsilosis following Exposure to Farnesol
Rossignol, T., Logue, M. E., Reynolds, K., Grenon, M., Lowndes, N. F., & Butler, G. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01438-06 · Cited by 75 · see citing works
Self-citationVale-Silva, L., Ischer, F., Leibundgut-Landmann, S., & Sanglard, D. (2013) · Infection and Immunity · doi:10.1128/iai.00074-13 · Cited by 65 · see citing works
Comparative Genomics of Two Sequential <i>Candida glabrata</i> Clinical Isolates
Vale-Silva, L., Beaudoing, E., Tran, V. D. T., & Sanglard, D. (2017) · G3 Genes|Genomes|Genetics · doi:10.1534/g3.117.042887 · Cited by 61 · see citing works
Gregori, C., Schüller, C., Roetzer, A., Schwarzmüller, T., Ammerer, G., & Kuchler, K. (2007) · Eukaryotic Cell · doi:10.1128/ec.00106-07 · Cited by 57 · see citing works
Khatib, R., Johnson, L. B., Fakih, M. G., Riederer, K., & Briski, L. (2016) · Mycoses · doi:10.1111/myc.12531 · Cited by 48 · see citing works
Halliwell, S., Smith, M. C. A., Muston, P., Holland, S. L., & Avery, S. V. (2011) · Eukaryotic Cell · doi:10.1128/ec.05232-11 · Cited by 46 · see citing works
Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae
Kołaczkowska, A., Kołaczkowski, M., Delahodde, A., & Goffeau, A. (2002) · Molecular Genetics and Genomics · doi:10.1007/s00438-002-0642-0 · Cited by 40 · see citing works
Monteiro, P. T., Pais, P., Costa, C., Manna, S., Sá-Correia, I., & Teixeira, M. C. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkw817 · Cited by 40 · see citing works
Bernardo, R., Cunha, D. V., Wang, C., Pereira, L., Silva, S. M., Salazar, S. B., Schröder, M., Okamoto, M., Takahashi‐Nakaguchi, A., Chibana, H., et al. (2017) · G3 Genes Genomes Genetics · doi:10.1534/g3.116.034660 · Cited by 30 · see citing works
Self-citationCunha, D. V., Salazar, S. B., Lopes, M., & Mira, N. P. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00259 · Cited by 19 · see citing works
Self-citationXu, N., Ye, C., Chen, X., Liu, J., Liu, L., & Chen, J. (2016) · Scientific Reports · doi:10.1038/srep34893 · Cited by 15 · see citing works
Draft Genome Sequences of Candida glabrata Isolates 1A, 1B, 2A, 2B, 3A, and 3B
Håvelsrud, O. E., & Gaustad, P. (2017) · Genome Announcements · doi:10.1128/genomea.00328-16 · Cited by 9 · see citing works
Carreté, L., Księżopolska, E., Pegueroles, C., Gómez-Molero, E., Saus, E., Iraola‐Guzmán, S., Loska, D., Bader, O., Fairhead, C., & Gabaldón, T. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/105791 · Cited by 2 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Antifungal Drug Resistance: Molecular Mechanisms in <i>Candida albicans</i> and Beyond
Lee, Y., Puumala, E., Robbins, N., & Cowen, L. E. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00199 · Cited by 801 · see citing works
Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens
Ksiezopolska, E., & Gabaldón, T. (2018) · Genes · doi:10.3390/genes9090461 · Cited by 230 · see citing works
Fungal Resistance to Echinocandins and the MDR Phenomenon in Candida glabrata
Healey, K. R., & Perlin, D. S. (2018) · Journal of Fungi · doi:10.3390/jof4030105 · Cited by 194 · see citing works
Candida glabrata: A Lot More Than Meets the Eye
Kumar, K., Askari, F., Sahu, M. S., & Kaur, R. (2019) · Microorganisms · doi:10.3390/microorganisms7020039 · Cited by 128 · see citing works
Divergent Approaches to Virulence in C. albicans and C. glabrata: Two Sides of the Same Coin
Galocha, M., Pais, P., Cavalheiro, M., Pereira, D., Viana, R., & Teixeira, M. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092345 · Cited by 105 · see citing works
Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata
Healey, K., & Perlin, D. S. (2018) · doi:10.20944/preprints201808.0306.v1 · Cited by 194 · see citing works
Cavalheiro, M., Costa, C., Silva-Dias, A., Miranda, I. M., Wang, C., Pais, P., Pinto, S. N., Mil-Homens, D., Sato-Okamoto, M., Takahashi-Nakaguchi, A., et al. (2019) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00995-18 · Cited by 42 · see citing works
Self-citationCandida glabrata’s Genome Plasticity Confers a Unique Pattern of Expressed Cell Wall Proteins
López-Fuentes, E., Gutiérrez-Escobedo, G., Timmermans, B., Van Dijck, P., De Las Peñas, A., & Castaño, I. (2018) · Journal of Fungi · doi:10.3390/jof4020067 · Cited by 35 · see citing works
Leiva-Peláez, O., Gutiérrez-Escobedo, G., López-Fuentes, E., Cruz-Mora, J., De Las Peñas, A., & Castaño, I. (2018) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2018.05.005 · Cited by 10 · see citing works
- Authors
- Salazar, S. B., Wang, C., Münsterkötter, M., Okamoto, M., Takahashi-Nakaguchi, A., Chibana, H., Lopes, M. M., Güldener, U., Butler, G., & Mira, N. P.
- Affiliations
- University of Lisbon (PT)
- University College Dublin (IE)
- Helmholtz Munich (DE)
- Chiba University (JP)
- Corresponding author
- Mira, Nuno Pereira
- ORCID
- Venue
- FEMS Yeast Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-10-26
- Volume
- 18
- Issue
- 1
- ISSN
- 1567-1356 (ISSN-L)
- 1567-1364
- OpenAlex
- W2765511622
- Cited by
- 31
- References
- 39
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 11 · 2018: 7
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEMS Yeast Research (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- FCT-Portuguese Foundation Science Foundation Ireland (UID/BIO/04565/2013, 12IA1343)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Yeasts and Rust Fungi Studies
- Keywords
- Candida glabrata, azole resistance, fluconazole resistance, voriconazole resistance, gain-of-function mutations, transcriptional regulation, organic acid tolerance, adhesin genes, host adaptation, clinical isolates, carbohydrate metabolism, nitrogen metabolism, sulfur metabolism
- MeSH terms
- Alleles, Antifungal Agents, Candidiasis, Gene Frequency, Humans, Fluconazole, Gene Expression Regulation, Fungal, Genome, Fungal, Gene Deletion, Computational Biology, Gene Expression Profiling, Genomics, Drug Resistance, Fungal, Candida glabrata, Host-Pathogen Interactions, Molecular Sequence Annotation, Transcriptome, Voriconazole
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