Interface of Candida albicans Biofilm Matrix-Associated Drug Resistance and Cell Wall Integrity Regulation
Open accessAbstract
Candida albicans frequently infects medical devices by growing as a biofilm, i.e., a community of adherent organisms entrenched in an extracellular matrix. During biofilm growth, Candida spp. acquire the ability to resist high concentrations of antifungal drugs. One recently recognized biofilm resistance mechanism involves drug sequestration by matrix β-1,3 glucan. Using a candidate gene approach, we investigated potential C. albicans β-1,3-glucan regulators, based on their homology to Saccharomyces cerevisiae , including SMI1 and protein kinase C (PKC) pathway components. We identified a role for the SMI1 in biofilm matrix glucan production and development of the associated drug resistance phenotype. This pathway appears to act through transcription factor Rlmp and glucan synthase Fks1p. The phenotypes of these mutant biofilms mimicked those of the smi1 Δ/ smi1 Δ biofilm, and overexpression of FKS1 in the smi1 Δ/ smi1 Δ mutant restored the biofilm resistant phenotype. However, control of this pathway is distinct from that of the upstream PKC pathway because the pkc1 Δ/ pkc1 Δ, bck1 Δ/ bck1 Δ, mkk2 Δ/ mkk2 Δ, and mkc1 Δ/ mkc1 Δ biofilms retained the resistant phenotype of the parent strain. In addition, resistance to cell-perturbing agents and gene expression data do not support a significant role for the cell wall integrity pathway during the biofilm formation. Here we show that Smi1p functions in conjunction with Rlm1p and Fks1p to produce drug-sequestering biofilm β-glucan. Our work provides new insight into how the C. albicans biofilm matrix production and drug resistance pathways intersect with the planktonic cell wall integrity pathway. This novel connection helps explain how pathogens in a multicellular biofilm community are protected from anti-infective therapy.
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Two known transcriptional regulators of biofilm matrix production in C. albicans are Rlm1 and Zap1.
“Two known transcriptional regulators of biofilm matrix production in C. albicans are Rlm1 and Zap1.”
From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [136]
Deletion of RLM1 causes a reduction in matrix levels.
“Deletion of RLM1 causes a reduction in matrix levels (136), whereas deletion of ZAP1 leads to an increase in the accumulation of extracellular matrix material, probably by upregulating the glucoamylases Gca1 and Gca2 (144).”
From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [136]
The transcriptional regulator Rlm1 contributes to antifungal drug resistance by regulating the expression of FKS1.
“The transcriptional regulator Rlm1 (discussed above) contributes to antifungal drug resistance by regulating the expression of FKS1 (136).”
From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [136]
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- Authors
- Nett, J. E., Sanchez, H., Cain, M. T., Ross, K. M., & Andes, D. R.
- Affiliations
- University of Wisconsin–Madison (US)
- Department of Medicine, University of Wisconsin, Madison, Wisconsin
- Corresponding author
- Andes, David R.
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2011-12
- Volume
- 10
- Issue
- 12
- Pages
- 1660-1669
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC3232725
- OpenAlex
- W2138246367
- Cited by
- 168
- References
- 54
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 13 · 2021: 12 · 2020: 16 · 2019: 8 · 2018: 13 · 2017: 12 · 2016: 17 · 2015: 12 · 2014: 9 · 2013: 17 · 2012: 7
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL007899)
- National Institute of Allergy and Infectious Diseases (R01AI073289)
- 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, antifungal resistance, β-1,3-glucan, extracellular matrix, glucan synthase, protein kinase C pathway, cell wall integrity pathway, drug sequestration, medical device infections, biofilm formation
- MeSH terms
- Animals, Antifungal Agents, Candida albicans, Candidiasis, Cell Wall, Fungal Proteins, Glucosyltransferases, Protein Kinase C, Virulence, Fluconazole, Gene Expression Regulation, Fungal, Biofilms, Drug Resistance, Fungal, beta-Glucans, Mice, Rats, Gene Knockout Techniques, Catheters
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