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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AmB binds to ergosterol, forming microporous channels on the cell membrane and enabling the drug's fungicidal activity.
“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]
The Results report that AmB binds ergosterol and permeabilizes membranes, consistent with the binding and channel-forming parts of the claim. But the Results also show that a derivative unable to permeabilize membranes remains fungicidal, and the Discussion concludes that ergosterol binding—not channel formation—is primarily responsible for yeast killing. The claim therefore overstates the role of channels in AmB’s fungicidal activity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDownregulation of ergosterol may reduce exposure of AmB drug targets.
“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]
Polyenes act as a sponge extracting ergosterol from the fungal cell membrane, leading to pore formation, leakage of cellular components and fungal cell death.
“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]
Amphotericin B irreversibly binds to ergosterol, resulting in fungal cell death.
“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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- 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
- Physical Sciences › Chemistry › Organic Chemistry › 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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