Inhibition of nucleic acid biosynthesis makes little difference to formation of amphotericin B-tolerant persisters in Candida albicans biofilm
Open accessAbstract
Candida albicans persisters constitute a small subpopulation of biofilm cells and play a major role in recalcitrant chronic candidiasis; however, the mechanism underlying persister formation remains unclear. Persisters are often described as dormant, multidrug-tolerant, nongrowing cells. Persister cells are difficult to isolate and study not only due to their low levels in C. albicans biofilms but also due to their transient, reversible phenotype. In this study, we tried to induce persister formation by inducing C. albicans cells into a dormant state. C. albicans cells were pretreated with 5-fluorocytosine (planktonic cells, 0.8 μg ml −1 ; biofilm cells, 1 μg ml −1 ) for 6 h at 37°C, which inhibits nucleic acid and protein synthesis. Biofilms and planktonic cultures of eight C. albicans strains were surveyed for persisters after amphotericin B treatment (100 μg ml −1 for 24 h) and CFU assay. None of the planktonic cultures, with or without 5-fluorocytosine pretreatment, contained persisters. Persister cells were found in biofilms of all tested C. albicans strains, representing approximately 0.01 to 1.93% of the total population. However, the persister levels were not significantly increased in C. albicans biofilms pretreated with 5-fluorocytosine. These results suggest that inhibition of nucleic acid synthesis did not seem to increase the formation of amphotericin B-tolerant persisters in C. albicans biofilms.
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?
Dormancy alone is insufficient for the persistence development.
“demonstrating that dormancy alone is insufficient for the persistence development [43].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [43]
The Results and Discussion report that inducing dormancy through 5-fluorocytosine treatment did not significantly increase persister formation in the tested C. albicans biofilms. That supports a narrower, tentative version of the claim, but the paper studied only eight strains and explicitly says it is premature to rule out dormancy as a cause of fungal persisters. The cited sentence presents the conclusion more definitively and without that scope limitation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLive/dead staining can be applied to distinguish live and dead cells, reflecting the essence of persisters that survive exposure to fungicides.
“To solve these problems, live/dead staining method can be applied because of its ability to distinguish live/dead cells, which reflects the essence of persisters that survive exposure to fungicides.”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [43]
Experimental induction of dormancy through 5-fluorocytosine-mediated inhibition of nucleic acid and protein synthesis failed to enhance AmB persistence in C. albicans biofilm.
“Furthermore, experimental induction of dormancy through 5-fluorocytosine-mediated inhibition of nucleic acid and protein synthesis failed to enhance AmB persistence in C. albicans biofilm”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [43]
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
Persister cells, dormancy and infectious disease
Lewis, K. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1557 · Cited by 2,052 · see citing works
Lewis, K. (2010) · Annual Review of Microbiology · doi:10.1146/annurev.micro.112408.134306 · Cited by 1,858 · see citing works
Candida biofilms and their role in infection
Douglas, L. J. (2003) · Trends in Microbiology · doi:10.1016/s0966-842x(02)00002-1 · Cited by 1,150 · see citing works
Hospital-Acquired Candidemia: The Attributable Mortality and Excess Length of Stay
Wey, S. B. (1988) · Archives of Internal Medicine · doi:10.1001/archinte.1988.00380120094019 · Cited by 831 · see citing works
Multidrug Tolerance of Biofilms and Persister Cells
Lewis, K. (2008) · Current topics in microbiology and immunology · doi:10.1007/978-3-540-75418-3_6 · Cited by 807 · see citing works
Vermes, A. (2000) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/46.2.171 · Cited by 803 · see citing works
Ramage, G., Vande Walle, K., Wickes, B. L., & López-Ribot, J. L. (2001) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.45.9.2475-2479.2001 · Cited by 753 · see citing works
<i>Candida</i>Biofilms: an Update
Ramage, G., Saville, S. P., Thomas, D. P., & López-Ribot, J. L. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.4.633-638.2005 · Cited by 678 · see citing works
Colombo, A. L., Nucci, M., Park, B. J., Nouér, S. A., Arthington, B. A., da Matta, D. A., Warnock, D. W., & Morgan, J. (2006) · Journal of Clinical Microbiology · doi:10.1128/jcm.00773-06 · Cited by 525 · see citing works
<i>Candida albicans</i> Biofilms Produce Antifungal-Tolerant Persister Cells
LaFleur, M. D., Kumamoto, C. A., & Lewis, K. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00684-06 · Cited by 521 · see citing works
Ramage, G. (2002) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkf049 · Cited by 468 · see citing works
Regulation of Cell-Surface Genes and Biofilm Formation by the C. albicans Transcription Factor Bcr1p
Nobile, C. J., & Mitchell, A. P. (2005) · Current Biology · doi:10.1016/j.cub.2005.05.047 · Cited by 464 · see citing works
Mechanisms of <i>Candida</i> Biofilm Drug Resistance
Taff, H. T., Mitchell, K. F., Edward, J. A., & Andes, D. R. (2013) · Future Microbiology · doi:10.2217/fmb.13.101 · Cited by 422 · see citing works
Baillie, G. S. (2000) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/46.3.397 · Cited by 389 · see citing works
Arrested Protein Synthesis Increases Persister-Like Cell Formation
Kwan, B. W., Valenta, J. A., Benedik, M. J., & Wood, T. K. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02135-12 · Cited by 358 · see citing works
Biofilm lifestyle of <i>Candida:</i> a mini review
Seneviratne, C., Jin, L., & Samaranayake, L. (2008) · Oral Diseases · doi:10.1111/j.1601-0825.2007.01424.x · Cited by 317 · see citing works
Epidemiology of opportunistic fungal infections in Latin America
Nucci, M., Queiroz‐Telles, F., Tobón, A. M., Restrepo, A., & Colombo, A. L. (2010) · Clinical Infectious Diseases · doi:10.1086/655683 · Cited by 280 · see citing works
Recent insights into Candida albicans biofilm resistance mechanisms
Mathé, L., & Van Dijck, P. (2013) · Current Genetics · doi:10.1007/s00294-013-0400-3 · Cited by 271 · see citing works
A problem of persistence: still more questions than answers?
Balaban, N. Q., Gerdes, K., Lewis, K., & McKinney, J. D. (2013) · Nature Reviews Microbiology · doi:10.1038/nrmicro3076 · Cited by 263 · see citing works
Mode of action of 5-fluorocytosine and mechanisms of resistance
Polak, A., & Scholer, H. J. (2009) · Chemotherapy · doi:10.1159/000221854 · Cited by 250 · see citing works
Patients with Long-Term Oral Carriage Harbor High-Persister Mutants of <i>Candida albicans</i>
LaFleur, M. D., Qi, Q., & Lewis, K. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00860-09 · Cited by 237 · see citing works
Self-citationEffect of Growth Rate on Resistance of <i>Candida albicans</i> Biofilms to Antifungal Agents
Baillie, G. S., & Douglas, L. J. (1998) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.42.8.1900 · Cited by 234 · see citing works
Persister Cells: Molecular Mechanisms Related to Antibiotic Tolerance
Lewis, K. (2012) · Handbook of Experimental Pharmacology · doi:10.1007/978-3-642-28951-4_8 · Cited by 217 · see citing works
Bassetti, M., Taramasso, L., Nicco, E., Molinari, M. P., Mussap, M., & Viscoli, C. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024198 · Cited by 215 · see citing works
de Micheli, M., Billé, J., Schueller, C., & Sanglard, D. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.02814.x · Cited by 182 · see citing works
Wenzel, R. P., & Gennings, C. (2005) · Clinical Infectious Diseases · doi:10.1086/430923 · Cited by 158 · see citing works
(2013) · PubMed · Cited by 150 · see citing works
Mechanisms of action of 5-fluorocytosine
Waldorf, A. R., & Polak, A. (1983) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.23.1.79 · Cited by 141 · see citing works
Das, I., Nightingale, P., Patel, M., & Jumaa, P. (2011) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2011.06.006 · Cited by 136 · see citing works
Bondaryk, M., Kurzątkowski, W., & Staniszewska, M. (2013) · Advances in Dermatology and Allergology · doi:10.5114/pdia.2013.38358 · Cited by 126 · see citing works
“Persisters”: Survival at the Cellular Level
Dawson, C. C., Intapa, C., & Jabra‐Rizk, M. A. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002121 · Cited by 119 · see citing works
Superoxide dismutases are involved in Candida albicans biofilm persistence against miconazole
Bink, A., Vandenbosch, D., Coenye, T., Nelis, H., Cammue, B. P. A., & Thevissen, K. (2011) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00280-11 · Cited by 119 · see citing works
Adherence of <i>Candida albicans</i> to Silicone Induces Immediate Enhanced Tolerance to Fluconazole
Mateus, C., Crow, S. A., & Ahearn, D. G. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.9.3358-3366.2004 · Cited by 113 · see citing works
Absence of Amphotericin B-Tolerant Persister Cells in Biofilms of Some <i>Candida</i> Species
Al-Dhaheri, R. S., & Douglas, L. J. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01473-07 · Cited by 99 · see citing works
Apoptosis in Candida biofilms exposed to amphotericin B
Al-Dhaheri, R. S., & Douglas, L. J. (2010) · Journal of Medical Microbiology · doi:10.1099/jmm.0.015784-0 · Cited by 81 · see citing works
Qu, Y., Daley, A. J., Istivan, T. S., Rouch, D. A., & Deighton, M. A. (2010) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkq119 · Cited by 78 · see citing works
Emerging trends in candidemia: A higher incidence but a similar outcome
Fortün, J., Martín‐Dávila, P., de la Pedrosa, E. G., Pintado, V., Cobo, J., Fresco, G., Meije, Y., Ros, L., Álvarez, M. E. D., Luengo, J. D. M. L., et al. (2012) · Journal of Infection · doi:10.1016/j.jinf.2012.02.011 · Cited by 75 · see citing works
Mixed bloodstream infections involving bacteria and Candida spp.
Bouza, E., Burillo, A., Muñóz, P., Guinea, J., Marín, M., & Rodríguez‐Créixems, M. (2013) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkt099 · Cited by 75 · see citing works
Wu, Z., Liu, Y., Feng, X., Liu, Y., Wang, S., Zhu, X., Chen, Q., & Pan, S. (2014) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2013.11.011 · Cited by 53 · see citing works
Peng, S., & Lü, Y. (2012) · Journal of Critical Care · doi:10.1016/j.jcrc.2012.09.007 · Cited by 45 · see citing works
Recommendations for the management of candidemia in adults in Latin America
Nucci, M., Thompson-Moya, L., Guzmán-Blanco, M., Tiraboschi, I. N., Cortés, J. A., Echevarria, J. I., Sifuentes‐Osornio, J., Zurita, J., Santolaya, M. E., Matute, T. A., et al. (2013) · Revista Iberoamericana de Micología · doi:10.1016/j.riam.2013.05.007 · Cited by 41 · see citing works
Kazak, E., Akın, H., Ener, B., Sığırlı, D., Özkan, Ö., Gürcüoğlu, E., Yılmaz, E., Çelebi, S., Akçağlar, S., & Akalın, H. (2014) · Mycoses · doi:10.1111/myc.12209 · Cited by 39 · see citing works
Cortés, J. A., Reyes, P., Gómez, C., Cuervo, S. I., Rivas, P., Casas, C. A., & Sánchez, R. (2014) · The Brazilian Journal of Infectious Diseases · doi:10.1016/j.bjid.2014.06.009 · Cited by 38 · see citing works
Recommendations for the management of candidemia in children in Latin America
Santolaya, M. E., Telles, F. D. Q., Matute, T. A., Colombo, A. L., Zurita, J., Tiraboschi, I. N., Cortés, J. A., Thompson-Moya, L., Guzmán-Blanco, M., Sifuentes‐Osornio, J., et al. (2013) · Revista Iberoamericana de Micología · doi:10.1016/j.riam.2013.05.010 · Cited by 34 · see citing works
Luzzati, R., Cavinato, S., Deiana, M. L., Rosin, C., Maurel, C., & Borelli, M. (2014) · Aging Clinical and Experimental Research · doi:10.1007/s40520-014-0251-x · Cited by 32 · see citing works
Inhibition of Nucleotide Biosynthesis Potentiates the Antifungal Activity of Amphotericin B
Banerjee, D., Burkard, L., & Panepinto, J. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087246 · Cited by 26 · see citing works
Polak, A., & Wain, W. H. (2009) · Chemotherapy · doi:10.1159/000221992 · Cited by 25 · see citing works
Effects of 5-fluorocytosine on protein synthesis and amino acid pool inCandida albicans
Polak, A. (1974) · Medical Mycology · doi:10.1080/00362177485380451 · Cited by 21 · see citing works
Yang, C., Gong, W., Lu, J., Zhu, X., & Qi, Q. (2009) · Journal of Oral Pathology and Medicine · doi:10.1111/j.1600-0714.2009.00811.x · Cited by 20 · see citing works
Self-citation[Roles of drug efflux pump genes in the mechanism of Saccharomyces albicans biofilm drug tolerance].
Qi, Q., & Lafleur, M. D. (2009) · PubMed · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [42]CLSI. 2008. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard, 3rd ed CLSI document M27-A3. Clinical and Laboratory Standards Institute, Wayne, PA. [[Google Scholar](https://scholar.google.com/scholar_lookup?title=CLSI%20document%20M27-A3&publication_year=2008&)]
Cited by
Sorted by citations
Antifungal persistence: Clinical relevance and mechanisms
Wang, R., Lv, J., Chen, L., Zhao, Y., & Du, H. (2025) · PLoS pathogens · doi:10.1371/journal.ppat.1013456 · Cited by 12 · see citing works
“For example, using a scanning confocal microscope, fluorescein diacetate can stain live cells green, whereas propidium iodide (PI) stains dead cells red, enabling the visual identification of persisters [2,12,43].”
- Authors
- Sun, J., Liu, X., Jiang, G., & Qi, Q.
- Affiliations
- Shandong University (CN)
- Jinan Stomatological Hospital (CN)
- Shandong Provincial Key Laboratory of Oral Biomedicine, Shandong University, Jinan, Shandong, China
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-03
- Volume
- 59
- Issue
- 3
- Pages
- 1627-1633
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4325803
- OpenAlex
- W2076766593
- Cited by
- 6
- References
- 50
- Citations by year
- 2025: 2 · 2021: 1 · 2019: 1 · 2016: 1 · 2015: 1
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- 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 › Bacterial biofilms and quorum sensing
- Keywords
- Candida albicans, biofilm, persister cells, 5-fluorocytosine, dormancy, chronic candidiasis, antifungal resistance, planktonic cells
- MeSH terms
- Amphotericin B, Antifungal Agents, Candida albicans, Candidiasis, Flucytosine, Microbial Sensitivity Tests, Nucleic Acids, Biofilms
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
