Ospemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activities
Open accessAbstract
Azole antifungals are vital therapeutic options for treating invasive mycotic infections. However, the emergence of azole-resistant isolates combined with limited therapeutic options presents a growing challenge in medical mycology. To address this issue, we utilized microdilution checkerboard assays to evaluate nine stilbene compounds for their ability to interact synergistically with azole drugs, particularly against azole-resistant fungal isolates. Ospemifene displayed the most potent azole chemosensitizing activity, and its combination with itraconazole displayed broad-spectrum synergistic interactions against Candida albicans, Candida auris, Cryptococcus neoformans, and Aspergillus fumigatus (ΣFICI = 0.05–0.50). Additionally, in a Caenorhabditis elegans infection model, the ospemifene-itraconazole combination significantly reduced fungal CFU burdens in infected nematodes by ~75–96%. Nile Red efflux assays and RT-qPCR analysis suggest ospemifene interferes directly with fungal efflux systems, thus permitting entry of azole drugs into fungal cells. This study identifies ospemifene as a novel antifungal adjuvant that augments the antifungal activity of itraconazole against a broad range of fungal pathogens.
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Microdilution checkerboard assays were utilized, and the ΣFICI was calculated and interpreted as previously described.
“To evaluate the in vitro effectiveness of the AmB/LNP combination against a variety of Candida species, microdilution checkerboard assays were utilized, and the ΣFICI was calculated and interpreted as previously described [26,27].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant <i>Candida auris</i> (2024) · cites this paper as [27]
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References 52 · Cited by 33
- Authors
- Eldesouky, H. E., Salama, E. A., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N.
- Affiliations
- Purdue University West Lafayette (US)
- Zewail City of Science and Technology (EG)
- Corresponding author
- Mayhoub, Abdelrahman S.
- Seleem, Mohamed N.
- Venue
- Scientific Reports
- Published
- 2020-04-08
- Volume
- 10
- Issue
- 1
- Pages
- 6089-6089
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7142066
- OpenAlex
- W3015835414
- Cited by
- 33
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 3
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Purdue e-Pubs (Purdue University System) (submittedVersion)
- VTechWorks (Virginia Tech) (submittedVersion, cc-by)
- Greater South Information System
- Funders
- Purdue University
- University of Missouri
- University of Otago
- University of Missouri-Kansas City
- Centers for Disease Control and Prevention
- Health Science Center, University of Tennessee
- National Institute of Allergy and Infectious Diseases (R01AI141439)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- ospemifene, itraconazole, azole resistance, antifungal synergy, stilbene compounds, Candida albicans, Candida auris, Cryptococcus neoformans, Aspergillus fumigatus, Caenorhabditis elegans infection model, drug repurposing
- MeSH terms
- Antifungal Agents, Aspergillus fumigatus, Candida, Cryptococcus neoformans, Drug Synergism, Fungal Proteins, Tamoxifen, Itraconazole, ATP-Binding Cassette Transporters
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