The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
Candida albicans Biofilms Produce Antifungal-Tolerant Persister Cells
Open accessAbstract
Fungal pathogens form biofilms that are highly recalcitrant to antimicrobial therapy. The expression of multidrug resistance pumps in young biofilms has been linked to increased resistance to azoles, but this mechanism does not seem to underlie the resistance of mature biofilms that is a model of in vivo infection. The mechanism of drug resistance of mature biofilms remains largely unknown. We report that biofilms formed by the major human pathogen Candida albicans exhibited a strikingly biphasic killing pattern in response to two microbicidal agents, amphotericin B, a polyene antifungal, and chlorhexidine, an antiseptic, indicating that a subpopulation of highly tolerant cells, termed persisters, existed. The extent of killing with a combination of amphotericin B and chlorhexidine was similar to that observed with individually added antimicrobials. Thus, surviving persisters form a multidrug-tolerant subpopulation. Interestingly, surviving C. albicans persisters were detected only in biofilms and not in exponentially growing or stationary-phase planktonic populations. Reinoculation of cells that survived killing of the biofilm by amphotericin B produced a new biofilm with a new subpopulation of persisters. This suggests that C. albicans persisters are not mutants but phenotypic variants of the wild type. Using a stain for dead cells, rare dark cells were visible in a biofilm after amphotericin B treatment, and a bright and a dim population were physically sorted from this biofilm. Only the dim cells produced colonies, showing that this method allows the isolation of yeast persisters. Given that persisters formed only in biofilms, mutants defective in biofilm formation were examined for tolerance of amphotericin B. All of the known mutants affected in biofilm formation were able to produce normal levels of persisters. This finding indicates that attachment rather than formation of a complex biofilm architecture initiates persister formation. Bacteria produce multidrug-tolerant persister cells in both planktonic and biofilm populations, and it appears that yeasts and bacteria have evolved analogous strategies that assign the function of survival to a small part of the population. In bacteria, persisters are dormant cells. It remains to be seen whether attachment initiates dormancy that leads to the formation of fungal persisters. This study suggests that persisters may be largely responsible for the multidrug tolerance of fungal biofilms.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Currently, antifungal persistence is mainly identified in Candida-associated biofilms [2,32,33].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Antifungal persistence is most commonly observed in biofilm rather than in planktonic cells [2,33,34]”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 [2]
The cited source says what the claim attributes to it.
In the citing paper
“For example, C. albicans persister biofilms are recalcitrant to AmB and broad-spectrum antimicrobial agent chlorhexidine [2];”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“indicating that antifungal persistence is not solely dependent on matured biofilm structure formation [2].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“However, LaFleur and colleagues first reported that the biofilm-deficient double mutant strain efg1Δ/cph1Δ did not result in the reduction of AmB-triggered persisters”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [2]
In the citing paper
“Inside the biofilm cell population, persister cells form a unique group that is formed randomly, phenotypically dormant, highly tolerant to antifungal drugs [164], and which is a key mechanism of resistance in chronic infections [130].”
From Candida glabrata Biofilms: How Far Have We Come? (2017) · cites this paper as [164]
In the citing paper
“A minor subset of metabolically dormant yeast cells that stochastically arise as phenotypical variants within biofilms, persister cells are extremely resistant to antifungal drugs (100).”
From Candida albicans Biofilms and Human Disease (2015) · cites this paper as [100]
In the citing paper
“Although we know little about the formation and roles of persister cells in C. albicans biofilms, we do know that the drug resistance of persister cells is independent of cell membrane composition and efflux pump expression; rather, it is the result of the metabolically dormant state of the cells (88, 100).”
From Candida albicans Biofilms and Human Disease (2015) · cites this paper as [100]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Bacterial Persistence as a Phenotypic Switch
Balaban, N. Q., Merrin, J., Chait, R., Kowalik, L., & Leibler, S. (2004) · Science · doi:10.1126/science.1099390 · Cited by 2,952
Chandra, J., Kuhn, D. M., Mukherjee, P. K., Hoyer, L. L., McCormick, T., & Ghannoum, M. A. (2001) · Journal of Bacteriology · doi:10.1128/jb.183.18.5385-5394.2001 · Cited by 1,578
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
Persister cells and tolerance to antimicrobials
Keren, I., Kaldalu, N., Spoering, A. L., Wang, Y., & Lewis, K. (2003) · FEMS Microbiology Letters · doi:10.1016/s0378-1097(03)00856-5 · Cited by 1,094
Self-citationCandida Infections of Medical Devices
Kojic, E. M., & Darouiche, R. O. (2004) · Clinical Microbiology Reviews · doi:10.1128/cmr.17.2.255-267.2004 · Cited by 1,055
Spoering, A. L., & Lewis, K. (2001) · Journal of Bacteriology · doi:10.1128/jb.183.23.6746-6751.2001 · Cited by 907
Self-citationSpecialized Persister Cells and the Mechanism of Multidrug Tolerance in Escherichia coli
Keren, I., Shah, D., Spoering, A. L., Kaldalu, N., & Lewis, K. (2004) · Journal of Bacteriology · doi:10.1128/jb.186.24.8172-8180.2004 · Cited by 848
Self-citationKuhn, D. M., George, T., Chandra, J., Mukherjee, P. K., & Ghannoum, M. A. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.6.1773-1780.2002 · Cited by 775
Standardized Method for In Vitro Antifungal Susceptibility Testing of Candida albicans Biofilms
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
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
Research works printed but not linked: 1
- 10.1111/j.1574-6968.2002.tb11330.x · DOI · Paper page
Cited by
Sorted by citations
Persister cells, dormancy and infectious disease
Lewis, K. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1557 · Cited by 2,052
Self-citationLewis, K. (2010) · Annual Review of Microbiology · doi:10.1146/annurev.micro.112408.134306 · Cited by 1,858
Self-citationSardi, J. C. O., Scorzoni, L., Bernardi, T., Fusco-Almeida, A. M., & Mendes Giannini, M. J. S. (2013) · Journal of Medical Microbiology · doi:10.1099/jmm.0.045054-0 · Cited by 1,184
Candida albicans Biofilms and Human Disease
Nobile, C. J., & Johnson, A. D. (2015) · Annual Review of Microbiology · doi:10.1146/annurev-micro-091014-104330 · Cited by 1,057
Essential Oils and Antifungal Activity
Nazzaro, F., Fratianni, F., Coppola, R., & Feo, V. D. (2017) · Pharmaceuticals · doi:10.3390/ph10040086 · Cited by 889
Metadata
- Authors
- LaFleur, M. D., Kumamoto, C. A., & Lewis, K.
- Affiliations
- Northeastern University (US)
- Tufts University (US)
- Corresponding author
- Lewis, Kim
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2006-11
- Volume
- 50
- Issue
- 11
- Pages
- 3839-3846
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC1635216
- OpenAlex
- W2135493487
- Cited by
- 521
- References
- 52
- Citations by year
- 2026: 26 · 2025: 29 · 2024: 20 · 2023: 20 · 2022: 20 · 2021: 39 · 2020: 33 · 2019: 21 · 2018: 22 · 2017: 41 · 2016: 34 · 2015: 39 · 2014: 25 · 2013: 31 · 2012: 26
- FWCI
- 9.91
- 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 Institutes of Health
- Tufts University School of Medicine
- National Institute of General Medical Sciences (R01GM061162)
- National Institute of Allergy and Infectious Diseases (AI052805, R01AI052805)
- 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, antifungal tolerance, multidrug tolerance, amphotericin B, chlorhexidine, phenotypic variants, biofilm formation, cell attachment, dormancy, antifungal resistance
- MeSH terms
- Antifungal Agents, Candida albicans, Chlorhexidine, Disinfectants, Fluoresceins, Microbial Sensitivity Tests, Microscopy, Fluorescence, Phenotype, Biofilms, Drug Resistance, Multiple, Fungal
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
