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Amphotericin primarily kills yeast by simply binding ergosterol
Open accessAbstract
Amphotericin B (AmB) is a prototypical small molecule natural product that can form ion channels in living eukaryotic cells and has remained refractory to microbial resistance despite extensive clinical utilization in the treatment of life-threatening fungal infections for more than half a century. It is now widely accepted that AmB kills yeast primarily via channel-mediated membrane permeabilization. Enabled by the iterative cross-coupling-based synthesis of a functional group deficient derivative of this natural product, we have discovered that channel formation is not required for potent fungicidal activity. Alternatively, AmB primarily kills yeast by simply binding ergosterol, a lipid that is vital for many aspects of yeast cell physiology. Membrane permeabilization via channel formation represents a second complementary mechanism that further increases drug potency and the rate of yeast killing. Collectively, these findings ( i ) reveal that the binding of a physiologically important microbial lipid is a powerful and clinically validated antimicrobial strategy that may be inherently refractory to resistance, ( ii ) illuminate a more straightforward path to an improved therapeutic index for this clinically vital but also highly toxic antifungal agent, and ( iii ) suggest that the capacity for AmB to form protein-like ion channels might be separable from its cytocidal effects.
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In the citing paper
“AmB binds to ergosterol, forming microporous channels on the cell membrane and enabling the drug’s fungicidal activity.”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [64]
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“Downregulation of ergosterol may therefore reduce the exposure of AmB drug targets [64].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [64]
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“These amphipathic compounds act as a sponge extracting ergosterol from the fungal cell membrane, leading to the formation of pores, causing leakage of cellular components and ultimately death of the fungal cell [32,33].”
From Antifungal therapy of Candida biofilms: Past, present and future (2023) · cites this paper as [33]
In the citing paper
“Amphotericin B (AMB), a polyene class of antifungal drug, irreversibly binds to ergosterol, resulting in fungal cell death.”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [615]
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Metadata
- Authors
- Gray, K. C., Palacios, D. S., Dailey, I., Endo, M. M., Uno, B. E., Wilcock, B. C., & Burke, M. D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-01-17
- Volume
- 109
- Issue
- 7
- Pages
- 2234-2239
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3289339
- OpenAlex
- W1987640473
- Cited by
- 608
- References
- 50
- Citations by year
- 2026: 42 · 2025: 42 · 2024: 34 · 2023: 49 · 2022: 45 · 2021: 56 · 2020: 53 · 2019: 50 · 2018: 32 · 2017: 44 · 2016: 44 · 2015: 40 · 2014: 36 · 2013: 30 · 2012: 11
- FWCI
- 24.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Bristol-Myers Squibb
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM080436, GM080436)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Antimicrobial agents and applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- amphotericin B, ergosterol binding, yeast cell death, antifungal mechanism, ion channel formation, membrane permeabilization, fungal drug resistance, natural product derivatives, therapeutic index, antifungal toxicity
- MeSH terms
- Amphotericin B, Antifungal Agents, Ergosterol, Saccharomyces cerevisiae
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