Amphotericin forms an extramembranous and fungicidal sterol sponge

Anderson, Thomas M; Clay, Mary C; Cioffi, Alexander G; Diaz, Katrina A; Hisao, Grant S; Tuttle, Marcus D; Nieuwkoop, Andrew J; Comellas, Gemma; Maryum, Nashrah; Wang, Shu; Uno, Brice E; Wildeman, Erin L; Gonen, Tamir; Rienstra, Chad M; Burke, Martin D

doi:10.1038/nchembio.1496

Cited by 528Lipid Membrane Structure and BehaviorAntifungal resistance and susceptibilityAntimicrobial agents and applications

Amphotericin forms an extramembranous and fungicidal sterol sponge

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Anderson, Thomas M, Clay, Mary C, Cioffi, Alexander G, Diaz, Katrina A, Hisao, Grant S, Tuttle, Marcus D, Nieuwkoop, Andrew J, Comellas, Gemma +7 more·2014·Nature Chemical Biology

DOI 10.1038/nchembio.1496PMC PMC3992202

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Abstract

For over 50 years, amphotericin has remained the powerful but highly toxic last line of defense in treating life-threatening fungal infections in humans with minimal development of microbial resistance. Understanding how this small molecule kills yeast is thus critical for guiding development of derivatives with an improved therapeutic index and other resistance-refractory antimicrobial agents. In the widely accepted ion channel model for its mechanism of cytocidal action, amphotericin forms aggregates inside lipid bilayers that permeabilize and kill cells. In contrast, we report that amphotericin exists primarily in the form of large, extramembranous aggregates that kill yeast by extracting ergosterol from lipid bilayers. These findings reveal that extraction of a polyfunctional lipid underlies the resistance-refractory antimicrobial action of amphotericin and suggests a roadmap for separating its cytocidal and membrane-permeabilizing activities. This new mechanistic understanding is also guiding development of what are to our knowledge the first derivatives of amphotericin that kill yeast but not human cells.

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Amphotericin B kills growing and non-growing fungal cells by sponging essential ergosterols from the plasma membrane and generating lethal pores.
“Amphotericin B kills growing and non-growing fungal cells by sponging essential ergosterols from the plasma membrane and generating lethal pores (43).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [43]
The Discussion supports killing by extraction of ergosterol from yeast membranes, but contradicts the claim that lethal pore formation is also required: it says ergosterol binding can kill cells in the absence of channel activity. The Online Methods describe stationary-phase cultures, but do not establish the claim about both growing and non-growing cells. (LLM, conf=0.88)
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Amphotericin B destroys the cell membrane through extracting ergosterol from lipid bilayers and is fungicidal.
“Fluconazole does not have an antifungal effect as strong as amphotericin B, the latter which destroys the cell membrane through extracting ergosterol from lipid bilayers and is fungicidal.”
From The synthesis, regulation, and functions of sterols inCandida albicans: Well-known but still lots to learn (2016) · cites this paper as [89]
The Results section (‘AmB extracts Erg from and thereby kills yeast cells’; page not provided) reports that amphotericin B extracts ergosterol from yeast membranes and that extraction parallels cell killing. The paper does not establish that this process destroys the cell membrane; it distinguishes cell killing from membrane permeabilization. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Amphotericin B kills C. albicans and C. glabrata with biphasic kinetics after a brief lag.
“Amphotericin B, which kills fungal cells by depleting ergosterol and creating pores in the plasma membrane (43), was also found to kill C. albicans and C. glabrata with biphasic kinetics after a brief lag (Fig. 8, red symbols).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [43]
Citation 43 attaches to the mechanism clause, not the biphasic-kinetics finding attributed to Fig. 8. The Results section says amphotericin B extracts ergosterol and thereby kills yeast, but the Discussion says channel formation is not required for cell killing, contrary to presenting pore creation as part of the killing mechanism. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Amphotericin B binds or sequesters ergosterol-related lipids to exert its fungicidal activity.
“AMB binds or sequesters ergosterol-related lipids to exert its fungicidal activity46,47.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [47]
Fluconazole does not have an antifungal effect as strong as amphotericin B.
“Fluconazole does not have an antifungal effect as strong as amphotericin B, the latter which destroys the cell membrane through extracting ergosterol from lipid bilayers and is fungicidal.”
From The synthesis, regulation, and functions of sterols inCandida albicans: Well-known but still lots to learn (2016) · cites this paper as [89]
The Abstract describes amphotericin B as a powerful antifungal that kills yeast by extracting ergosterol from lipid bilayers. It does not compare its antifungal effect with fluconazole; searches for fluconazole and for an azole-versus-amphotericin comparison found no passage addressing that comparison. (LLM, conf=0.75)
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Authors: Anderson, T. M., Clay, M. C., Cioffi, A. G., Diaz, K. A., Hisao, G. S., Tuttle, M. D., Nieuwkoop, A. J., Comellas, G., Maryum, N., Wang, S., Uno, B. E., Wildeman, E. L., Gonen, T., Rienstra, C. M., & Burke, M. D.
Affiliations: University of Illinois Urbana-Champaign (US)
Howard Hughes Medical Institute (US)
Corresponding author: Rienstra, Chad M
Burke, Martin D
ORCID: Clay, Mary C
Cioffi, Alexander G
Hisao, Grant S
Tuttle, Marcus D
Nieuwkoop, Andrew J
Wang, Shu
Gonen, Tamir
Rienstra, Chad M
Burke, Martin D
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2014-03-30
Volume: 10
Issue: 5
Pages: 400-406
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.1496
PMC: PMC3992202
OpenAlex: W2139472183
Cited by: 528
References: 58
Citations by year: 2026: 47 · 2025: 53 · 2024: 61 · 2023: 45 · 2022: 36 · 2021: 64 · 2020: 42 · 2019: 38 · 2018: 33 · 2017: 32 · 2016: 38 · 2015: 28 · 2014: 11
FWCI: 14.89
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Chemical Biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Howard Hughes Medical Institute
National Institute of General Medical Sciences (R01GM080436)
National Institute of Diabetes and Digestive and Kidney Diseases (F30DK081272)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Physical Sciences › Chemistry › Organic Chemistry › Antimicrobial agents and applications
Keywords: amphotericin, ergosterol, fungal membranes, antifungal mechanism, yeast cell death, membrane permeabilization, sterol extraction, ion channel models
MeSH terms: Amphotericin B, Antifungal Agents, Lipid Bilayers, Magnetic Resonance Spectroscopy, Permeability, Sterols

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Amphotericin forms an extramembranous and fungicidal sterol sponge

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