Novel high-throughput screen against Candida albicans identifies antifungal potentiators and agents effective against biofilms
Open accessAbstract
OBJECTIVES: Microbial adhesion and biofilms have important implications for human health and disease. Candida albicans is an opportunistic pathogen which forms drug-resistant biofilms that contribute to the recalcitrance of disease. We have developed a high-throughput screen for potentiators of clotrimazole, a common therapy for Candida infections, including vaginitis and thrush. The screen was performed against C. albicans biofilms grown in microtitre plates in order to target the most resilient forms of the pathogen. METHODS: Biofilm growth, in individual wells of 384-well plates, was measured using the metabolic indicator alamarBlue® and found to be very consistent and reproducible. This assay was used to test the effect of more than 120 000 small molecule compounds from the NIH Molecular Libraries Small Molecule Repository, and compounds that enhanced the activity of clotrimazole or acted on the biofilms alone were identified as hits. RESULTS: Nineteen compounds (0.016% hit rate) were identified and found to cause more than 30% metabolic inhibition of biofilms compared with clotrimazole alone, which had a modest effect on biofilm viability at the concentration tested. Hits were confirmed for activity against biofilms with dose-response measurements. Several compounds had increased activity in combination with clotrimazole, including a 1,3-benzothiazole scaffold that exhibited a >100-fold improvement against biofilms of three separate C. albicans isolates. Cytotoxicity experiments using human fibroblasts confirmed the presence of lead molecules with favourable antifungal activity relative to cytotoxicity. CONCLUSIONS: We have validated a novel approach to identify antifungal potentiators and completed a high-throughput screen to identify small molecules with activity against C. albicans biofilms. These small molecules may specifically target the biofilm and make currently available antifungals more effective.
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The LaFleur group identified 19 potentiators of clotrimazole biofilm activity against C. albicans using HTS.
“Using HTS, they identified a total of 19 potentiators of clotrimazole biofilm activity against C. albicans, which were subsequently validated for their ability to inhibit biofilms alone, and in the presence of clotrimazole [55].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [55]
Screens of chemical libraries have identified compounds that disrupt formation and/or maintenance of biofilms.
“Screens of chemical libraries have identified compounds that disrupt formation and/or maintenance of biofilms (25, 101, 185, 210).”
From <i>Candida albicans</i> Biofilms and Human Disease (2015) · cites this paper as [101]
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- Authors
- LaFleur, M. D., Lucumi, E., Napper, A. D., Diamond, S. L., & Lewis, K.
- Affiliations
- Northeastern University (US)
- University of Pennsylvania (US)
- Corresponding author
- LaFleur, M. D.
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-01-28
- Volume
- 66
- Issue
- 4
- Pages
- 820-826
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- PMC
- PMC3058565
- OpenAlex
- W2171759023
- Cited by
- 59
- References
- 47
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 6 · 2013: 5 · 2012: 2
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Human Genome Research Institute (U54HG003915, HG003915)
- National Institute of General Medical Sciences (R01GM061162, GM061162)
- National Institute of Allergy and Infectious Diseases (R43AI074258, R44AI074258)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Candida albicans, biofilm, clotrimazole, high-throughput screening, small molecules, benzothiazole, antifungal resistance, cytotoxicity, combination antifungal therapy
- MeSH terms
- Antifungal Agents, Candida albicans, Cell Adhesion, Cell Survival, Clotrimazole, Drug Interactions, Drug Evaluation, Preclinical, Humans, Microbial Sensitivity Tests, Oxazines, Staining and Labeling, Xanthenes, Biofilms, High-Throughput Screening Assays
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