Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans
Open accessAbstract
Candidiasis, which presents a substantial risk to human well‐being, is frequently treated with azoles. However, drug‐drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)‐approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle‐mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole‐mediated liver enzyme inhibition and avoids export‐mediated drug resistance in C. albicans .
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The MIC of FLC is significantly decreased in C. albicans upc2∆/upc2∆ mutant.
“A previous study demonstrated that the minimum inhibitory concentration (MIC) of FLC was significantly decreased in C. albicans mutant with deletions in the UPC2 gene (upc2∆/upc2∆) [12,19].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [19]
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Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches
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“A dose-matrix titration assay was conducted as previously described to assess the synergistic effects of two drugs against C. albicans [19,24].”
Self-citation
- Authors
- Zhen, C., Wang, L., Feng, Y., Whiteway, M., Hang, S., Yu, J., Lu, H., & Jiang, Y.
- Affiliations
- Tongji University (CN)
- Concordia University (CA)
- Corresponding author
- Lu, Hui
- Jiang, Yuanying
- Venue
- Advanced Science
- Publisher
- Wiley
- Published
- 2024-07-12
- Volume
- 11
- Issue
- 35
- Pages
- e2406473-e2406473
- ISSN
- 2198-3844 (ISSN-L)
- PMC
- PMC11425263
- OpenAlex
- W4400582752
- Cited by
- 16
- References
- 75
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 1
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Advanced Science (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Key Research and Development Program of China (2022YFC2303004, 2021YFC2300404)
- National Natural Science Foundation of China (82020108032)
- 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 › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- otilonium bromide, Candida albicans, antifungal drug repurposing, plasma membrane localization, Sec31, azole resistance, drug-drug interactions, CYP3A4 inhibition, candidiasis
- MeSH terms
- Quaternary Ammonium Compounds, Animals, Antifungal Agents, Autophagy, Candida albicans, Candidiasis, Cell Membrane, Ergosterol, Humans, Microbial Sensitivity Tests
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