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.
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Antifungal persistence is mainly identified in Candida-associated biofilms.
“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]
The Abstract and Discussion (page not supplied in our copy) report that C. albicans persisters were detected in biofilms, not in the planktonic cultures tested. The paper supports that specific finding, but does not establish the broader claim that antifungal persistence is mainly identified in Candida-associated biofilms generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAntifungal persistence is most commonly observed in biofilm rather than in planktonic cells.
“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]
The Results and Discussion report persisters in C. albicans biofilms but not in the exponential- or stationary-phase planktonic cultures tested. This supports the biofilm–planktonic comparison for C. albicans, but not the broader claim about antifungal persistence generally. Page numbers were not provided with the passages. (LLM, conf=0.84)
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 [2]
C. albicans persister biofilms are recalcitrant to AmB and the broad-spectrum antimicrobial agent chlorhexidine.
“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]
Antifungal persistence is not solely dependent on matured biofilm structure formation.
“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 biofilm-deficient double mutant strain efg1Δ/cph1Δ did not result in the reduction of AmB-triggered persisters.
“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]
Persister cells form a unique group inside the biofilm cell population, are formed randomly, are phenotypically dormant, highly tolerant to antifungal drugs, and are a key mechanism of resistance in chronic infections.
“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]
Persister cells are a minor subset of metabolically dormant yeast cells that stochastically arise as phenotypical variants within biofilms and are extremely resistant to antifungal drugs.
“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 <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [100]
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.
“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 <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [100]
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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 · see citing works
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 · 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
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 1,099 · see citing works
Self-citation<i>Candida</i> 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 · see citing works
Spoering, A. L., & Lewis, K. (2001) · Journal of Bacteriology · doi:10.1128/jb.183.23.6746-6751.2001 · Cited by 907 · see citing works
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 857 · see citing works
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 765 · 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
Persisters: a distinct physiological state of E. coli
Khodursky, A. B., Zhang, Z., Devang, S., Kaldalu, N., Kurg, K., & Lewis, K. (2006) · Digital Repository Service (Northeastern University) · doi:10.1186/1471-2180-6-53 · Cited by 630 · see citing works
Self-citation“Sleeping Beauty”: Quiescence in Saccharomyces cerevisiae
Gray, J. V., Petsko, G. A., Johnston, G. C., Ringe, D., Singer, R. A., & Werner‐Washburne, M. (2004) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.68.2.187-206.2004 · Cited by 573 · see citing works
Mukherjee, P. K., Chandra, J., Kuhn, D. M., & Ghannoum, M. A. (2003) · Infection and Immunity · doi:10.1128/iai.71.8.4333-4340.2003 · Cited by 511 · see citing works
Comparison of Biofilms Formed byCandidaalbicansandCandidaparapsilosison Bioprosthetic Surfaces
Kuhn, D. M., Chandra, J., Mukherjee, P. K., & Ghannoum, M. A. (2002) · Infection and Immunity · doi:10.1128/iai.70.2.878-888.2002 · Cited by 485 · see citing works
A Dose-Response Study of Antibiotic Resistance in Pseudomonas aeruginosa Biofilms
Brooun, A., Liu, S., & Lewis, K. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.3.640-646.2000 · Cited by 474 · see citing works
Self-citationRamage, 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
Baillie, G. S. (2000) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/46.3.397 · Cited by 389 · see citing works
García-Sánchez, S., Aubert, S., Iraqui, I., Janbon, G., Ghigo, J.-M., & d'Enfert, C. (2004) · Eukaryotic Cell · doi:10.1128/ec.3.2.536-545.2004 · Cited by 353 · see citing works
Uses and Limitations of the XTT Assay in Studies of Candida Growth and Metabolism
Kuhn, D. M., Balkis, M. M., Chandra, J., Mukherjee, P. K., & Ghannoum, M. A. (2003) · Journal of Clinical Microbiology · doi:10.1128/jcm.41.1.506-508.2003 · Cited by 339 · see citing works
Ramage, G., VandeWalle, K., López-Ribot, J. L., & Wickes, B. L. (2002) · FEMS Microbiology Letters · doi:10.1016/s0378-1097(02)00853-4 · Cited by 334 · see citing works
Fungal Biofilms and Drug Resistance
Jabra-Rizk, M. A., Falkler, W. A., & Meiller, T. F. (2004) · Emerging Infectious Diseases · doi:10.3201/eid1001.030119 · Cited by 292 · see citing works
de Nobel, H., Ruiz, C., Martı́n, H., Morris, W. L., Brul, S., Molina, M., & Klis, F. M. (2000) · Microbiology · doi:10.1099/00221287-146-9-2121 · Cited by 269 · see citing works
Ramage, G., VandeWalle, K., Bachmann, S. P., Wickes, B. L., & Lopez-Ribot, J. L. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.11.3634-3636.2002 · Cited by 238 · see citing works
ALTERNATIVECANDIDA ALBICANSLIFESTYLES: Growth on Surfaces
Kumamoto, C. A., & Vinces, M. D. (2005) · Annual Review of Microbiology · doi:10.1146/annurev.micro.59.030804.121034 · Cited by 236 · see citing works
Self-citationVázquez‐Laslop, N., Lee, H., & Neyfakh, A. A. (2006) · Journal of Bacteriology · doi:10.1128/jb.188.10.3494-3497.2006 · Cited by 231 · see citing works
Ascospore Formation in the YeastSaccharomyces cerevisiae
Neiman, A. M. (2005) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.69.4.565-584.2005 · Cited by 226 · see citing works
MUKHERJEE, P., & Chandra, J. (2004) · Drug Resistance Updates · doi:10.1016/j.drup.2004.09.002 · Cited by 222 · see citing works
The biofilm glycocalyx as a resistance factor
Hoyle, B. D., Jaß, J., & Costerton, J. W. (1990) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/26.1.1 · Cited by 219 · see citing works
Kumamoto, C. A. (2002) · Current Opinion in Microbiology · doi:10.1016/s1369-5274(02)00371-5 · Cited by 217 · see citing works
Self-citationA contact-activated kinase signals Candida albicans invasive growth and biofilm development
Kumamoto, C. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407097102 · Cited by 210 · see citing works
Self-citationBiofilms, Infection, and Antimicrobial Therapy
(2005) · CRC Press eBooks · doi:10.1201/9781420028232 · Cited by 168 · see citing works
Candida biofilms: antifungal resistance and emerging therapeutic options.
Kuhn, D. M., & Ghannoum, M. A. (2004) · PubMed · Cited by 166 · see citing works
[48] Candida biofilms and their susceptibility to antifungal agents
Baillie, G. S., & Douglas, L. (1999) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(99)10050-8 · Cited by 160 · see citing works
Candida albicans Biofilm-Defective Mutants
Richard, M. L., Nobile, C. J., Bruno, V. M., & Mitchell, A. P. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.8.1493-1502.2005 · Cited by 157 · see citing works
Candida biofilm: a well-designed protected environment
Mukherjee, P. K., Zhou, G., Munyon, R., & Ghannoum, M. A. (2005) · Medical Mycology · doi:10.1080/13693780500107554 · Cited by 149 · see citing works
New Aspects in the Molecular Basis of Polymer-Associated Infections due to Staphylococci
von Eiff, C., Heilmann, C., & Peters, G. (1999) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s100960050417 · Cited by 128 · see citing works
Candida albicans Biofilms: More Than Filamentation
Lopez-Ribot, J. L. (2005) · Current Biology · doi:10.1016/j.cub.2005.06.020 · Cited by 116 · see citing works
Biofilms of Candida albicans and their associated resistance to antifungal agents.
Ramage, G., Wickes, B. L., & Lopez-Ribot, J. L. (2001) · PubMed · Cited by 114 · 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
Effect of cell cycle position on thermotolerance in Saccharomyces cerevisiae
Plesset, J., Ludwig, J. R., Cox, B. S., & McLaughlin, C. S. (1987) · Journal of Bacteriology · doi:10.1128/jb.169.2.779-784.1987 · Cited by 111 · see citing works
Giusani, A. D., Vinces, M. D., & Kumamoto, C. A. (2002) · Genetics · doi:10.1093/genetics/160.4.1749 · Cited by 96 · see citing works
Self-citationBasrani, B. R. (2005) · Australian Endodontic Journal · doi:10.1111/j.1747-4477.2005.tb00221.x · Cited by 88 · see citing works
Théraud, M., Bédouin, Y., Guiguen, C., & Gangneux, J. (2004) · Journal of Medical Microbiology · doi:10.1099/jmm.0.05474-0 · Cited by 84 · see citing works
In Vitro Method To Study Antifungal Perfusion in Candida Biofilms
Samaranayake, Y. H., Ye, J., Yau, J. Y. Y., Cheung, B. P. K., & Samaranayake, L. P. (2005) · Journal of Clinical Microbiology · doi:10.1128/jcm.43.2.818-825.2005 · Cited by 83 · see citing works
Bagiński, M., Sternal, K., Czub, J., & Borowski, E. (2005) · Acta Biochimica Polonica · doi:10.18388/abp.2005_3426 · Cited by 82 · see citing works
Yeast cell death during DNA damage arrest is independent of caspase or reactive oxygen species
Wysocki, R., & Kron, S. J. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405016 · Cited by 79 · see citing works
Martin, S. W., Douglas, L. M., & Konopka, J. B. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.7.1191-1202.2005 · Cited by 66 · see citing works
Induction, Morphogenesis, and Germination of the Chlamydospore of Candida albicans
Jansons, V. K., & Nickerson, W. J. (1970) · Journal of Bacteriology · doi:10.1128/jb.104.2.910-921.1970 · Cited by 65 · see citing works
Marchetti, O., Moreillon, P., Entenza, J. M., Vouillamoz, J., Glauser, M. P., Billé, J., & Sanglard, D. (2003) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.47.5.1565-1570.2003 · Cited by 57 · see citing works
Persisters: Specialized Cells Responsible for Biofilm Tolerance to Antimicrobial Agents
Lewis, K., Spoering, A. L., Kaldalu, N., Keren, I., & Shah, D. (2005) · CRC Press eBooks · doi:10.1201/9781420028232-18 · Cited by 17 · see citing works
Self-citationLa caspofungine : du mécanisme d'action aux applications thérapeutiques
Datry, A., & Bart–Delabesse, E. (2005) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2005.05.012 · Cited by 14 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [8]Datry, A., and E. Bart-Delabesse. 2006. Caspofungin: mode of action and therapeutic applications. Rev. Med. Interne 27:32-39. [DOI] [PubMed] [Google Scholar]
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 · see citing works
Self-citationLewis, K. (2010) · Annual Review of Microbiology · doi:10.1146/annurev.micro.112408.134306 · Cited by 1,858 · see citing works
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 · see citing works
<i>Candida albicans</i> 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 · see citing works
Essential Oils and Antifungal Activity
Nazzaro, F., Fratianni, F., Coppola, R., & Feo, V. D. (2017) · Pharmaceuticals · doi:10.3390/ph10040086 · Cited by 854 · 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
Self-citationCandida albicans biofilms: development, regulation, and molecular mechanisms
Gulati, M., & Nobile, C. J. (2016) · Microbes and Infection · doi:10.1016/j.micinf.2016.01.002 · Cited by 738 · see citing works
Tariq, S., Wani, S., Rasool, W., Shafi, K., Bhat, M. A., Prabhakar, A., Shalla, A. H., & Rather, M. A. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.103580 · Cited by 715 · see citing works
Candida Biofilms: Threats, Challenges, and Promising Strategies
Cavalheiro, M., & Teixeira, M. C. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00028 · Cited by 690 · see citing works
Multimetal resistance and tolerance in microbial biofilms
Harrison, J. J., Ceri, H., & Turner, R. J. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1774 · Cited by 666 · see citing works
Persister formation in Staphylococcus aureus is associated with ATP depletion
Conlon, B. P., Rowe, S. E., Gandt, A. B., Nuxoll, A. S., Donegan, N. P., Zalis, E. A., Clair, G., Adkins, J., Cheung, A. L., & Lewis, K. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.51 · Cited by 656 · see citing works
Self-citationDevelopment and regulation of single- and multi-species Candida albicans biofilms
Lohse, M. B., Gulati, M., Johnson, A. D., & Nobile, C. J. (2018) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2017.107 · Cited by 643 · see citing works
Mulcahy, L. R., Burns, J. L., Lory, S. J., & Lewis, K. (2010) · Journal of Bacteriology · doi:10.1128/jb.01651-09 · Cited by 621 · see citing works
Self-citationGenetic control of Candida albicans biofilm development
Finkel, J. S., & Mitchell, A. P. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2475 · Cited by 613 · see citing works
Ramage, G., Rajendran, R., Sherry, L., & Williams, C. (2012) · International Journal of Microbiology · doi:10.1155/2012/528521 · Cited by 583 · see citing works
Regulatory circuitry governing fungal development, drug resistance, and disease.
Shapiro, R. S., Robbins, N., & Cowen, L. E. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00045-10 · Cited by 576 · see citing works
How to build a biofilm: a fungal perspective
Blankenship, J. R., & Mitchell, A. P. (2006) · Current Opinion in Microbiology · doi:10.1016/j.mib.2006.10.003 · Cited by 530 · see citing works
Molecular mechanisms of antimicrobial tolerance and resistance in bacterial and fungal biofilms
Acker, H. V., Dijck, P. V., & Coenye, T. (2014) · Trends in Microbiology · doi:10.1016/j.tim.2014.02.001 · Cited by 527 · see citing works
Pathogenesis ofCandida albicansbiofilm
Tsui, C., Kong, E. F., & Jabra‐Rizk, M. A. (2016) · Pathogens and Disease · doi:10.1093/femspd/ftw018 · Cited by 487 · see citing works
Our Current Understanding of Fungal Biofilms
Ramage, G., Mowat, E., Jones, B., Williams, C., & Lopez-Ribot, J. (2009) · Critical Reviews in Microbiology · doi:10.3109/10408410903241436 · Cited by 483 · see citing works
Fanning, S., & Mitchell, A. P. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002585 · Cited by 465 · see citing works
Microbial Persistence and the Road to Drug Resistance
Cohen, N. R., Lobritz, M. A., & Collins, J. J. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.05.009 · Cited by 459 · see citing works
Molecular Evolution of Antifungal Drug Resistance
Robbins, N., Caplan, T., & Cowen, L. E. (2017) · Annual Review of Microbiology · doi:10.1146/annurev-micro-030117-020345 · Cited by 441 · see citing works
Fauvart, M., De Groote, V. N., & Michiels, J. (2011) · Journal of Medical Microbiology · doi:10.1099/jmm.0.030932-0 · Cited by 425 · see citing works
Resistance Toward Chlorhexidine in Oral Bacteria – Is There Cause for Concern?
Cieplik, F., Jakubovics, N. S., Buchalla, W., Maisch, T., Hellwig, E., & Al-Ahmad, A. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.00587 · Cited by 424 · 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
Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis
Scorzoni, L., de Paula e Silva, A. C. A., Marcos, C. M., Assato, P. A., de Melo, W. C. M. A., de Oliveira, H. C., Costa-Orlandi, C. B., Mendes-Giannini, M. J. S., & Fusco-Almeida, A. M. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00036 · Cited by 418 · see citing works
Biofilm of Candida albicans : formation, regulation and resistance
Pereira, R., Fontenelle, R. O. D. S., de Brito, É. H. S., & de Morais, S. M. (2020) · Journal of Applied Microbiology · doi:10.1111/jam.14949 · Cited by 388 · see citing works
Formation, physiology, ecology, evolution and clinical importance of bacterial persisters
den Bergh, B. V., Fauvart, M., & Michiels, J. J. (2017) · FEMS Microbiology Reviews · doi:10.1093/femsre/fux001 · Cited by 380 · see citing works
Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells
Pu, Y., Zhao, Z., Li, Y., Zou, J., Ma, Q., Zhao, Y., Ke, Y., Zhu, Y., Chen, H., Baker, M. A. B., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.03.035 · Cited by 379 · see citing works
Bet Hedging in Yeast by Heterogeneous, Age-Correlated Expression of a Stress Protectant
Levy, S. F., Ziv, N., & Siegal, M. L. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001325 · Cited by 371 · see citing works
Effects of Chlorhexidine mouthwash on the oral microbiome
Bescós, R., Ashworth, A., Clarke, C., Brookes, Z. L. S., Belfield, L., Rodiles, A., Casas‐Agustench, P., Farnham, G., Liddle, L., Burleigh, M. C., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61912-4 · Cited by 351 · see citing works
Microbial phenotypic heterogeneity and antibiotic tolerance
Dhar, N., & McKinney, J. D. (2007) · Current Opinion in Microbiology · doi:10.1016/j.mib.2006.12.007 · Cited by 336 · 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
The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress
Gefen, O., & Balaban, N. Q. (2009) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2008.00156.x · Cited by 313 · see citing works
The evolution of fungal drug resistance: modulating the trajectory from genotype to phenotype.
Cowen, L. E. (2008) · Nature Reviews Microbiology · doi:10.1038/nrmicro1835 · Cited by 311 · see citing works
Candida Species Biofilms’ Antifungal Resistance
Silva, S. M., Rodrigues, C. F., Araújo, D., Rodrigues, M. E., & Henriques, M. (2017) · Journal of Fungi · doi:10.3390/jof3010008 · Cited by 308 · see citing works
Concepts and Principles of Photodynamic Therapy as an Alternative Antifungal Discovery Platform
Dai, T., Fuchs, B. B., Coleman, J. J., Prates, R. A., Astrakas, C., Denis, T. G. S., Ribeiro, M. S., Mylonakis, E. E., Hamblin, M. R., & Tegos, G. P. (2012) · Frontiers in Microbiology · doi:10.3389/fmicb.2012.00120 · Cited by 295 · see citing works
A Candida Biofilm-Induced Pathway for Matrix Glucan Delivery: Implications for Drug Resistance
Taff, H. T., Nett, J. E., Zarnowski, R., Ross, K. M., Sanchez, H., Cain, M. T., Hamaker, J., Mitchell, A. P., & Andes, D. R. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002848 · Cited by 291 · see citing works
McCarty, T. P., & Pappas, P. G. (2016) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2015.10.013 · Cited by 285 · see citing works
Sanglard, D., Coste, A., & Ferrari, S. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00578.x · Cited by 285 · see citing works
Antifungal drug-resistance mechanisms in Candida biofilms
Kaur, J., & Nobile, C. J. (2022) · Current Opinion in Microbiology · doi:10.1016/j.mib.2022.102237 · Cited by 279 · see citing works
Role of oxidative stress in persister tolerance
Wu, Y., Vulić, M., Keren, I., & Lewis, K. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00921-12 · Cited by 276 · see citing works
Self-citationRoscetto, E., Contursi, P., Vollaro, A., Fusco, S., Notomista, E., & Catania, M. R. (2018) · Scientific Reports · doi:10.1038/s41598-018-35530-0 · Cited by 272 · see citing works
Immune defence to invasive fungal infections: A comprehensive review
Pathakumari, B., Liang, G., & Liu, W. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110550 · Cited by 272 · 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
Rosenberg, A., Ene, I. V., Bibi, M., Zakin, S., Segal, E. S., Ziv, N., Dahan, A. M., Colombo, A. L., Bennett, R. J., & Berman, J. (2018) · Nature Communications · doi:10.1038/s41467-018-04926-x · Cited by 270 · see citing works
Candida glabrata: A review of its features and resistance
Rodrigues, C. F., Silva, S., & Henriques, M. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-2009-3 · Cited by 268 · see citing works
Strategy to combat biofilms: a focus on biofilm dispersal enzymes
Wang, S., Zhao, Y., Breslawec, A. P., Liang, T., Deng, Z., Kuperman, L. L., & Yu, Q. (2023) · npj Biofilms and Microbiomes · doi:10.1038/s41522-023-00427-y · Cited by 265 · see citing works
Candidemia and Invasive Candidiasis
McCarty, T. P., White, C. M., & Pappas, P. G. (2021) · Infectious Disease Clinics of North America · doi:10.1016/j.idc.2021.03.007 · Cited by 260 · see citing works
Fungal Biofilms, Drug Resistance, and Recurrent Infection
Desai, J. V., Mitchell, A. P., & Andes, D. R. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019729 · Cited by 252 · see citing works
Use of Antimicrobial Peptides Against Microbial Biofilms: Advantages and Limits
Batoni, G., Maisetta, G., Brancatisano, F. L., Esin, S., & Campa, M. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711794088399 · Cited by 251 · see citing works
Kim, Y., & Wood, T. K. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.11.033 · Cited by 243 · see citing works
Hoefs, S., Mogavero, S., & Hube, B. (2016) · The Journal of Microbiology · doi:10.1007/s12275-016-5514-0 · Cited by 238 · 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-citationFungal Biofilms and Polymicrobial Diseases
Costa-Orlandi, C. B., Sardi, J. D. C. O., Pitangui, N. D. S., de Oliveira, H. C., Scorzoni, L., Galeane, M. C., Medina‐Alarcón, K. P., Melo, W., Marcelino, M., Braz, J. D., et al. (2017) · Journal of Fungi · doi:10.3390/jof3020022 · Cited by 237 · see citing works
Persisters, persistent infections and the Yin–Yang model
Zhang, Y. (2014) · Emerging Microbes & Infections · doi:10.1038/emi.2014.3 · Cited by 231 · see citing works
Candida biofilms and oral candidosis: treatment and prevention
Williams, D. W., Kuriyama, T., Silva, S. M., Malic, S., & Lewis, M. A. O. (2010) · Periodontology 2000 · doi:10.1111/j.1600-0757.2009.00338.x · Cited by 220 · 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
Self-citationPhotodynamic inactivation of biofilm: taking a lightly colored approach to stubborn infection
de Melo, W. C., Avci, P., Moritz, M. N. D. O., Gupta, A. K., Vecchio, D., Sadasivam, M., Chandran, R., Huang, Y., Yin, R., Perussi, L. R., et al. (2013) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.2013.811861 · Cited by 206 · see citing works
Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms
Delattin, N., Cammue, B. P., & Thevissen, K. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.13.189 · Cited by 189 · see citing works
Polke, M., Hube, B., & Jacobsen, I. D. (2015) · Advances in applied microbiology · doi:10.1016/bs.aambs.2014.12.002 · Cited by 188 · see citing works
Pharmacodynamics, Population Dynamics, and the Evolution of Persistence in Staphylococcus aureus
Johnson, P. J., & Levin, B. R. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003123 · Cited by 187 · see citing works
Vediyappan, G., Rossignol, T., & d'Enfert, C. (2010) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01638-09 · Cited by 183 · see citing works
Anti-Candida albicans natural products, sources of new antifungal drugs: A review
Zida, A., Bamba, S., Yacouba, A., Ouedraogo-Traoré, R., & Guiguemdé, R. T. (2016) · Journal de Mycologie Médicale · doi:10.1016/j.mycmed.2016.10.002 · Cited by 182 · see citing works
Martins, M., Henriques, M., Lopez‐Ribot, J. L., & Oliveira, R. (2012) · Mycoses · doi:10.1111/j.1439-0507.2011.02047.x · Cited by 174 · see citing works
Thymol inhibits Candida albicans biofilm formation and mature biofilm
Braga, P. C., Culici, M., Alfieri, M. F., & Sasso, M. D. (2008) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2007.12.013 · Cited by 170 · see citing works
Antifungal drug resistance of oral fungi
Niimi, M., Firth, N. A., & Cannon, R. D. (2010) · Odontology · doi:10.1007/s10266-009-0118-3 · Cited by 169 · see citing works
Terpenoids of plant origin inhibit morphogenesis, adhesion, and biofilm formation byCandida albicans
Raut, J. S., Shinde, R. B., Chauhan, N. M., & Karuppayil, S. M. (2012) · Biofouling · doi:10.1080/08927014.2012.749398 · Cited by 169 · see citing works
Nett, J. E., Sanchez, H., Cain, M. T., Ross, K. M., & Andes, D. R. (2011) · Eukaryotic Cell · doi:10.1128/ec.05126-11 · Cited by 168 · see citing works
Khan, A. U., Khan, S., Azam, & Alam, F. (2012) · International Journal of Nanomedicine · doi:10.2147/ijn.s31219 · Cited by 166 · see citing works
Role for Cell Density in Antifungal Drug Resistance in <i>Candida albicans</i> Biofilms
Perumal, P., Mekala, S., & Chaffin, W. L. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01237-06 · Cited by 165 · see citing works
Antifungal susceptibility of Candida albicans in biofilms
Tobudic, S., Kratzer, C., Lassnigg, A. M., & Presterl, E. (2011) · Mycoses · doi:10.1111/j.1439-0507.2011.02076.x · Cited by 165 · see citing works
Molecular mechanisms and clinical implications of bacterial persistence
Michiels, J. E., den Bergh, B. V., Verstraeten, N., & Michiels, J. J. (2016) · Drug Resistance Updates · doi:10.1016/j.drup.2016.10.002 · Cited by 164 · see citing works
Development and Validation of an In Vivo Candida albicans Biofilm Denture Model
Nett, J. E., Marchillo, K., Spiegel, C. A., & Andes, D. R. (2010) · Infection and Immunity · doi:10.1128/iai.00480-10 · Cited by 161 · see citing works
Approaches for the inhibition and elimination of microbial biofilms using macromolecular agents
Blackman, L. D., Qu, Y., Cass, P., & Locock, K. E. S. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00986e · Cited by 161 · see citing works
Contributions of the Biofilm Matrix to Candida Pathogenesis
Nett, J. E., & Andes, D. R. (2020) · Journal of Fungi · doi:10.3390/jof6010021 · Cited by 158 · see citing works
Persistence: mechanisms for triggering and enhancing phenotypic variability
Balaban, N. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.10.001 · Cited by 156 · see citing works
Effects of chlorhexidine mouthwash on the oral microbiome
Brookes, Z. L. S., Belfield, L., Ashworth, A., Casas‐Agustench, P., Raja, M., Pollard, A. J., & Bescós, R. (2021) · Journal of Dentistry · doi:10.1016/j.jdent.2021.103768 · Cited by 154 · see citing works
Nett, J. E., Cain, M. T., Crawford, K., & Andes, D. R. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.02273-10 · Cited by 153 · see citing works
Drug resistance in eukaryotic microorganisms
Fairlamb, A. H., Gow, N. A. R., Matthews, K. R., & Waters, A. P. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.92 · Cited by 152 · see citing works
Molecular and Cellular Mechanisms That Lead to Candida Biofilm Formation
ten Cate, J. M., Klis, F. M., Pereira‐Cenci, T., Wim Crielaard, A., & de Groot, P. W. J. (2009) · Journal of Dental Research · doi:10.1177/0022034508329273 · Cited by 150 · see citing works
Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance
Kowalski, C. H., Morelli, K. A., Schultz, D., Nadell, C. D., & Cramer, R. A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2003700117 · Cited by 149 · see citing works
Xu, X., Li, X., Yuan, G., Wang, Y., Qu, Y., & Zhou, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-25714-z · Cited by 147 · see citing works
Marques, C. N. H., Morozov, A., Planzos, P., & Zelaya, H. M. (2014) · Applied and Environmental Microbiology · doi:10.1128/aem.01576-14 · Cited by 143 · see citing works
Highlights in pathogenic fungal biofilms
Sardi, J. D. C. O., Pitangui, N. D. S., Rodríguez-Arellanes, G., Taylor, M. L., Fusco‐Almeida, A. M., & Mendes‐Giannini, M. J. S. (2013) · Revista Iberoamericana de Micología · doi:10.1016/j.riam.2013.09.014 · Cited by 142 · see citing works
Li, W., Shi, Q., Dai, H., Liang, Q. D., Xie, X., Huang, X.-M., Zhao, G.-Z., & Zhang, L. (2016) · Scientific Reports · doi:10.1038/srep22805 · Cited by 138 · see citing works
Fan, F., Liu, Y., Liu, Y., Lv, R., Sun, W., Ding, W., Cai, Y., Li, W., Liu, X., & Qu, W. (2022) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2022.106673 · Cited by 137 · see citing works
Fungal persister cells: The basis for recalcitrant infections?
Wuyts, J., Van Dijck, P., & Holtappels, M. (2018) · PLOS Pathogens · doi:10.1371/journal.ppat.1007301 · Cited by 136 · see citing works
Novel persistence genes in Pseudomonas aeruginosa identified by high-throughput screening
Groote, V. N. D., Verstraeten, N., Fauvart, M., Kint, C. I., Verbeeck, A. M., Beullens, S., Cornélis, P., & Michiels, J. J. (2009) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2009.01657.x · Cited by 134 · see citing works
Walraven, C. J., & Lee, S. A. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01351-12 · Cited by 132 · see citing works
In Vitro Culturing and Screening of Candida albicans Biofilms
Gulati, M., Lohse, M. B., Ennis, C. L., Gonzalez, R. E., Perry, A. M., Bapat, P. S., Arevalo, A. V., Rodríguez, D. L., & Nobile, C. J. (2018) · Current Protocols in Microbiology · doi:10.1002/cpmc.60 · Cited by 132 · see citing works
Candida glabrata Biofilms: How Far Have We Come?
Rodrigues, C., Rodrigues, M., Silva, S., & Henriques, M. (2017) · Journal of Fungi · doi:10.3390/jof3010011 · Cited by 129 · see citing works
Dijck, P. V., Sjollema, J., Cammue, B. P. A., Lagrou, K., Berman, J. G., d’Enfert, C., Andes, D. R., Arendrup, M. C., Brakhage, A. A., Calderone, R., et al. (2018) · Microbial Cell · doi:10.15698/mic2018.07.638 · Cited by 129 · see citing works
Biofilm formation by<b><i>Aspergillus fumigatus</i></b>
Kaur, S., & Singh, S. (2013) · Medical Mycology · doi:10.3109/13693786.2013.819592 · Cited by 128 · see citing works
Efficacy of Ethanol against Candida albicans and Staphylococcus aureus Polymicrobial Biofilms
Peters, B. M., Ward, R. M., Rane, H. S., Lee, S. A., & Noverr, M. C. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01599-12 · Cited by 124 · see citing works
Mowat, E., Lang, S., Williams, C., McCulloch, E., Jones, B., & Ramage, G. (2008) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkn402 · Cited by 124 · see citing works
Pierce, J. V., & Kumamoto, C. A. (2012) · mBio · doi:10.1128/mbio.00117-12 · Cited by 122 · see citing works
Self-citationCandida albicans biofilms: building a heterogeneous, drug-tolerant environment
Bonhomme, J., & d’Enfert, C. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.03.007 · Cited by 120 · see citing works
Seneviratne, C. J., da Silva, W. J., Jin, L., Samaranayake, Y. H., & Samaranayake, L. P. (2009) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2009.08.002 · Cited by 120 · see citing works
- 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
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