The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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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Citations
Cites
Antibiotic resistance is ancient
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Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis
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Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry
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Antibacterial agents based on the cyclic d,l-α-peptide architecture
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Taubes, G. (2008) · Science · doi:10.1126/science.321.5887.356 · Cited by 757
How do the polyene macrolide antibiotics affect the cellular membrane properties?
Bolard, J. (1986) · Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes · doi:10.1016/0304-4157(86)90002-x · Cited by 757
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Self-citationAn Alternative Bactericidal Mechanism of Action for Lantibiotic Peptides That Target Lipid II
Hasper, H. E., Kramer, N. E., Smith, L., Hillman, J. D., Zachariah, C., Kuipers, O. P., KRUIJFF, B. D., & Breukink, E. J. (2006) · Science · doi:10.1126/science.1129818 · Cited by 502
Gillis, E. P., & Burke, M. D. (2007) · Journal of the American Chemical Society · doi:10.1021/ja0716204 · Cited by 488
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Ferreira, T. G., Souza, T. D. F., Andrade, N. B., Fajardo, J. B., Vianna, M. H., Lemos, A. S. O., Polo, A. B., Diniz, I. O. M., Comitre, M. R. C., Lima, G. L. D. S., et al. (2026) · SSRN Electronic Journal · doi:10.2139/ssrn.7578659
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BindingDB Entry 50044288: Multitarget drug discovery for tuberculosis and other infectious diseases.
BindingDB (2015) · UC San Diego · doi:10.7270/q27p90zn
BindingDB (2025) · UC San Diego · doi:10.7270/q2r21600
BindingDB Entry 50002345: Emerging New Targets for the Treatment of Resistant Fungal Infections.
BindingDB (2020) · UC San Diego · doi:10.7270/q26112x4
Determining the Mode of Action of Ibomycin: A Novel Antifungal Compound
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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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