Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis
Open accessAbstract
ABSTRACT Among emerging non- albicans Candida species, Candida parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ERG2 , ERG5 , ERG6 , ERG11 , ERG24 , ERG25 , and UPC2 . Whole-genome sequencing revealed that the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin-intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins.
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?
ERG3 mutations leading to depletion of ergosterol and accumulation of less toxic sterols when ERG11 is inhibited have been implicated in cross-resistance between azoles and polyenes in S. cerevisiae and C. albicans and between echinocandins and azoles in C. parapsilosis.
“ERG3 mutations leading to the depletion of ergosterol and the accumulation of less toxic sterols when ERG11 is inhibited have been implicated in cross-resistance between azoles and polyenes in S. cerevisiae and C. albicans40, 41, 42, 43 and between echinocandins and azoles in C. parapsilosis.44,45”
From Narrow mutational signatures drive acquisition of multidrug resistance in the fungal pathogen Candida glabrata (2021) · cites this paper as [44]
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
National Committee for Clinical Laboratory Standards
Bruck, E. (1980) · PEDIATRICS · doi:10.1542/peds.65.1.187 · Cited by 14,736 · see citing works
A rapid and simple method for preparation of RNA from Saccharomyces cerevisiae
Schmitt, M. E., Brown, T. A., & Trumpower, B. L. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.10.3091 · Cited by 1,344 · see citing works
Denning, D. W. (2003) · The Lancet · doi:10.1016/s0140-6736(03)14472-8 · Cited by 1,131 · see citing works
Candida parapsilosis , an Emerging Fungal Pathogen
Trofa, D. P., Gácser, A., & Nosanchuk, J. D. (2008) · Clinical Microbiology Reviews · doi:10.1128/cmr.00013-08 · Cited by 862 · see citing works
The SAT1 flipper, an optimized tool for gene disruption in Candida albicans
Reuß, O., Vik, Å., Kolter, R., & Morschhäuser, J. (2004) · Gene · doi:10.1016/j.gene.2004.06.021 · Cited by 744 · see citing works
JBrowse: A next-generation genome browserPreprint
Skinner, M. E., Uzilov, A. V., Stein, L. D., Mungall, C., & Holmes, I. H. (2009) · Genome Research · doi:10.1101/gr.094607.109 · Cited by 718 · see citing works
Park, S., Kelly, R., Kahn, J. N., Robles, J., Hsu, M.-J., Register, E., Li, W., Vyas, V., Fan, H., Abruzzo, G., et al. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.8.3264-3273.2005 · Cited by 434 · see citing works
Pfaller, M. A., Andes, D. R., Diekema, D. J., Horn, D. L., Reboli, A. C., Rotstein, C., Franks, B., & Azie, N. E. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101510 · Cited by 396 · see citing works
Cleveland, A. A., Farley, M. M., Harrison, L. H., Stein, B., Hollick, R., Lockhart, S. R., Magill, S. S., Derado, G., Park, B. J., & Chiller, T. M. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cis697 · Cited by 366 · see citing works
Kelly, S. L., Lamb, D. C., Kelly, D. E., Manning, N. J., Loeffler, J., Hebart, H., Schumacher, U., & Einsele, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(96)01360-9 · Cited by 351 · see citing works
Self-citationGarcia-Effron, G., Katiyar, S. K., Park, S., Edlind, T. D., & Perlin, D. S. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00262-08 · Cited by 323 · see citing works
Lockhart, S. R., Iqbal, N., Cleveland, A. A., Farley, M. M., Harrison, L. H., Bolden, C. B., Baughman, W., Stein, B., Hollick, R., Park, B. J., et al. (2012) · Journal of Clinical Microbiology · doi:10.1128/jcm.01283-12 · Cited by 299 · see citing works
Kelly, S. L., Lamb, D. C., Corran, A. J., Baldwin, B. C., & Kelly, D. E. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1272 · Cited by 296 · see citing works
Self-citationSanglard, D., Coste, A., & Ferrari, S. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00578.x · Cited by 285 · see citing works
Stress, drugs, and evolution: the role of cellular signaling in fungal drug resistance.
Cowen, L. E., & Steinbach, W. J. (2008) · Eukaryotic Cell · doi:10.1128/ec.00041-08 · Cited by 285 · see citing works
Moudgal, V. V., Little, T., Boikov, D. A., & Vázquez, J. A. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.2.767-769.2005 · Cited by 241 · see citing works
Breakthrough invasive candidiasis in patients on micafungin.
Pfeiffer, C. D., Garcia-Effron, G., Zaas, A. K., Perfect, J. R., Perlin, D. S., & Alexander, B. D. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.02390-09 · Cited by 196 · see citing works
Disruption of Ergosterol Biosynthesis Confers Resistance to Amphotericin B inCandida lusitaniae
Young, L. Y., Hull, C. M., & Heitman, J. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.9.2717-2724.2003 · Cited by 184 · see citing works
Efflux pump proteins in antifungal resistance
Prasad, R., & Rawal, M. K. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00202 · Cited by 173 · see citing works
Martel, C. M., Parker, J. E., Bader, O., Weig, M., Gross, U., Warrilow, A. G. S., Rolley, N., Kelly, D. E., & Kelly, S. L. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00348-10 · Cited by 168 · see citing works
Self-citationAbbey, D. A., Funt, J., Lurie-Weinberger, M. N., Thompson, D. A., Regev, A., Myers, C. L., & Berman, J. (2014) · Genome Medicine · doi:10.1186/s13073-014-0100-8 · Cited by 147 · see citing works
Pfaller, M. A., Rhomberg, P. R., Messer, S. A., Jones, R. N., & Castanheira, M. (2015) · Diagnostic Microbiology and Infectious Disease · doi:10.1016/j.diagmicrobio.2015.04.008 · Cited by 127 · see citing works
Znaidi, S., Weber, S., Zin Al-Abdin, O., Bomme, P., Saidane, S., Drouin, S., Lemieux, S., De Deken, X., Robert, F., & Raymond, M. (2008) · Eukaryotic Cell · doi:10.1128/ec.00070-08 · Cited by 119 · see citing works
Grossman, N. T., Pham, C. D., Cleveland, A. A., & Lockhart, S. R. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.04613-14 · Cited by 112 · see citing works
Vale-Silva, L. A., Coste, A. T., Ischer, F., Parker, J. E., Kelly, S. L., Pinto, E., & Sanglard, D. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.05720-11 · Cited by 96 · see citing works
Self-citationBerkow, E. L., Manigaba, K., Parker, J. E., Barker, K. S., Kelly, S. L., & Rogers, P. D. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01358-15 · Cited by 95 · see citing works
Self-citationJensen, R. H., Astvad, K. M. T., Silva, L. V., Sanglard, D., Jørgensen, R., Nielsen, K. F., Mathiasen, E. G., Doroudian, G., Perlin, D. S., & Arendrup, M. C. (2015) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkv140 · Cited by 95 · see citing works
Hull, C. M., Bader, O., Parker, J. E., Weig, M., Gross, U., Warrilow, A. G. S., Kelly, D. E., & Kelly, S. L. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01145-12 · Cited by 90 · see citing works
Self-citationTranscriptional profiling of azole-resistant Candida parapsilosis strains
Silva, A. P., Miranda, I. M., Guida, A., Synnott, J., Rocha, R., Silva, R., Amorim, A., Pina-Vaz, C., Butler, G., & Rodrigues, A. G. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01127-10 · Cited by 86 · see citing works
Inactivation of Sterol Δ 5,6 -Desaturase Attenuates Virulence in Candida albicans
Chau, A. S., Gurnani, M., Hawkinson, R., Laverdière, M., Cacciapuoti, A. F., & McNicholas, P. M. (2005) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.49.9.3646-3651.2005 · Cited by 75 · see citing works
Miyazaki, Y., Geber, A., Miyazaki, H., Falconer, D., Parkinson, T., Hitchcock, C., Grimberg, B., Nyswaner, K., & Bennett, J. E. (1999) · Gene · doi:10.1016/s0378-1119(99)00263-2 · Cited by 71 · see citing works
Branco, J., Ola, M., Silva, R. M., Fonseca, E. S. S., Gomes, N. C., Martins-Cruz, C., Silva, A. P., Silva-Dias, A., Pina‐Vaz, C., Erraught, C., et al. (2017) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2017.02.002 · Cited by 68 · see citing works
Kabbara, N., Lacroix, C., Peffault de Latour, R., Socie, G., Ghannoum, M., & Ribaud, P. (2008) · Haematologica · doi:10.3324/haematol.11149 · Cited by 61 · see citing works
Branco, J., Silva, A. P., Silva, R. M., Silva-Dias, A., Pina‐Vaz, C., Butler, G., Rodrigues, A. G., & Miranda, I. M. (2015) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00842-15 · Cited by 49 · see citing works
Isolation of Yeast Genomic DNA for Southern Blot AnalysisPreprint
Amberg, D. C., Burke, D. J., & Strathern, J. N. (2006) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot4149 · Cited by 14 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- CLSI. 2008. Reference Method for Broth Microdilution Antifungal Susceptibility Testing of Yeasts; Approved Standard. CLSI Document M27-A3. 3 rd ed., Vol. 28. Wayne, Pennsylvania,. Clinical and Laboratory Standards Institute (CLSI).
Cited by
Sorted by citations
Resistance of Candida to azoles and echinocandins worldwide
Pristov, K. E., & Ghannoum, M. A. (2019) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2019.03.028 · Cited by 706 · see citing works
Candida parapsilosis: from genes to the bedside
Tóth, R., Nosek, J., Mora-Montes, H. M., Gabaldon, T., Bliss, J. M., Nosanchuk, J. D., Turner, S. A., Butler, G., Vágvölgyi, C., & Gácser, A. (2019) · Clinical Microbiology Reviews · doi:10.1128/cmr.00111-18 · Cited by 327 · see citing works
Carolus, H., Pierson, S., Muñoz, J. F., Subotić, A., Cruz, R. B., Cuomo, C. A., & Van Dijck, P. (2021) · mBio · doi:10.1128/mbio.03333-20 · Cited by 211 · see citing works
Rybak, J. M., Muñoz, J. F., Barker, K. S., Parker, J. E., Esquivel, B. D., Berkow, E. L., Lockhart, S. R., Gade, L., Palmer, G. E., White, T. C., et al. (2020) · mBio · doi:10.1128/mbio.00365-20 · Cited by 202 · see citing works
Self-citationRybak, J. M., Barker, K. S., Muñoz, J. F., Parker, J. E., Ahmad, S., Mokaddas, E., Abdullah, A., Elhagracy, R. S., Kelly, S. L., Cuomo, C. A., et al. (2022) · Clinical Microbiology and Infection · doi:10.1016/j.cmi.2021.11.024 · Cited by 120 · see citing works
Self-citationKsiezopolska, E., Schikora-Tamarit, M. À., Beyer, R., Nunez-Rodriguez, J. C., Schüller, C., & Gabaldón, T. (2021) · Current Biology · doi:10.1016/j.cub.2021.09.084 · Cited by 107 · see citing works
Burrack, L. S., Todd, R. T., Soisangwan, N., Wiederhold, N. P., & Selmecki, A. (2022) · mBio · doi:10.1128/mbio.00842-22 · Cited by 82 · see citing works
Self-citationSpettel, K., Barousch, W., Makristathis, A., Zeller, I., Nehr, M., Selitsch, B., Lackner, M., Rath, P.-M., Steinmann, J., & Willinger, B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210397 · Cited by 86 · see citing works
Comparative Genomics for the Elucidation of Multidrug Resistance in Candida lusitaniae
Kannan, A., Asner, S. A., Trachsel, E., Kelly, S., Parker, J., & Sanglard, D. (2019) · mBio · doi:10.1128/mbio.02512-19 · Cited by 63 · see citing works
Self-citationNing, Y., Xiao, M., Perlin, D. S., Zhao, Y., Lu, M., Li, Y., Luo, Z., Dai, R., Li, S., Xu, J., et al. (2023) · Emerging Microbes & Infections · doi:10.1080/22221751.2022.2153086 · Cited by 63 · see citing works
Ergosterol Biosynthesis and Regulation Impact the Antifungal Resistance and Virulence of Candida spp
Eliaš, D., Tóth Hervay, N., & Gbelská, Y. (2024) · Stresses · doi:10.3390/stresses4040041 · Cited by 63 · see citing works
Papp, C., Bohner, F., Kocsis, K., Varga, M., Szekeres, A., Bodai, L., Willis, J. R., Gabaldón, T., Tóth, R., Nosanchuk, J. D., et al. (2020) · mSphere · doi:10.1128/msphere.00821-20 · Cited by 42 · see citing works
- Authors
- Rybak, J. M., Dickens, C. M., Parker, J. E., Caudle, K. E., Manigaba, K., Whaley, S. G., Nishimoto, A. T., Luna-Tapia, A., Roy, S., Zhang, Q., Barker, K. S., Palmer, G. E., Sutter, T. R., Homayouni, R., Wiederhold, N. P., Kelly, S. L., & Rogers, P. D.
- Affiliations
- University of Tennessee Health Science Center (US)
- University of Memphis (US)
- Swansea University (GB)
- The University of Texas at San Antonio Health Science Center (US)
- ORCID
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2017-09
- Volume
- 61
- Issue
- 9
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC5571332
- OpenAlex
- W2689756537
- Cited by
- 53
- References
- 35
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 9 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 6 · 2019: 6 · 2018: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01 AI058145)
- 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
- Candida parapsilosis, antifungal resistance, azole resistance, echinocandin resistance, ergosterol biosynthesis, fluconazole, prosthetic valve endocarditis, UPC2, Candida albicans comparison, sterol profile
- MeSH terms
- Candida parapsilosis, Antifungal Agents, Azoles, Cross Infection, Ergosterol, Humans, Microbial Sensitivity Tests, Oxidoreductases, Fungemia, Genome, Fungal, Gene Dosage, Polymorphism, Single Nucleotide, Drug Resistance, Multiple, Fungal, Echinocandins
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
