A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance
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Background/Objectives: Candida albicans is the principal causative agent of candidiasis, the most common fungal infection in humans. Candidiasis represents the third-to-fourth most frequent nosocomial infection worldwide, as this normal commensal of humans causes opportunistic infections in an expanding population of immune- and medically compromised patients. These infections are frequently associated with biofilm formation, which complicates treatment and contributes to unacceptably high mortality rates. Methods: To address the pressing need for new antifungals, we have performed a high-content screen of 20,000 small molecules in a chemical library (NOVACore) to identify compounds that inhibit C. albicans biofilm formation, and conducted a series of follow-up studies to examine the in vitro and in vivo activity of the identified compounds. Results: The screen identified a novel series of diazaspiro-decane structural analogs that were largely represented among the bioactive compounds. Characterization of the leading compound from this series indicated that it inhibits processes associated with C. albicans virulence, most notably biofilm formation and filamentation, without having an effect on overall growth or eliciting resistance. This compound demonstrated in vivo activity in clinically relevant murine models of both invasive and oral candidiasis and as such represents a promising lead for antifungal drug development. Furthermore, these results provide proof of concept for the implementation of antivirulence approaches against C. albicans and other fungal infections that would be less likely to foster the emergence of resistance.
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Screening of chemical libraries identified diazaspiro-decane structural analogs (Pierce et al.) and compounds with a biaryl amide core (Romo et al.) as inhibitors of C. albicans biofilm formation.
“Pierce et al. reported on the identification of a new series of diazaspiro-decane structural analogs which were largely represented among the bioactive compounds [51]; whereas as reported in Romo et al. the two main hits belonged to a novel series of bioactive compounds with a common biaryl amide core structure [[52], [53], [54]].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [51]
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- Authors
- Pierce, C. G., Chaturvedi, A. K., Lazzell, A. L., Powell, A. T., Saville, S. P., McHardy, S. F., & Lopez-Ribot, J. L.
- Affiliations
- The University of Texas at San Antonio (US)
- Corresponding author
- Lopez-Ribot, Jose L
- Venue
- npj Biofilms and Microbiomes
- Published
- 2015-08-12
- Volume
- 1
- Issue
- 1
- ISSN
- 2055-5008 (ISSN-L)
- PMC
- PMC4681527
- OpenAlex
- W2419164965
- Cited by
- 124
- References
- 50
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 6 · 2023: 9 · 2022: 14 · 2021: 10 · 2020: 15 · 2019: 15 · 2018: 15 · 2017: 15 · 2016: 13
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- npj Biofilms and Microbiomes (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W911NF1110136)
- American Heart Association (11PRE5300004)
- National Institute of Allergy and Infectious Diseases (R01AI063256)
- National Institute of Dental and Craniofacial Research (R21DE017294, R01DE023510)
- National Institute on Minority Health and Health Disparities (G12MD007591)
- Army Research Office (W911NF-11-1-0136, W911NF, W911NF-11)
- 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, candidiasis, biofilm formation, filamentation, fungal virulence, antifungal drug development, small molecule inhibitors, high-content screening, anti-virulence strategies, antifungal resistance, oral candidiasis, invasive candidiasis, mouse infection model
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