title: Amphotericin forms an extramembranous and fungicidal sterol sponge.
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.
authors.affiliation: 1] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2].
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Anderson
authors.affiliation: 1] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2].
authors.forename: Mary C
authors.initials: MC
authors.lastname: Clay
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Cioffi
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Diaz
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Hisao
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Marcus D
authors.initials: MD
authors.lastname: Tuttle
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nieuwkoop
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Gemma
authors.initials: G
authors.lastname: Comellas
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Nashrah
authors.initials: N
authors.lastname: Maryum
authors.affiliation: 1] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Brice E
authors.initials: BE
authors.lastname: Uno
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Wildeman
authors.affiliation: Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA.
authors.forename: Tamir
authors.initials: T
authors.lastname: Gonen
authors.affiliation: 1] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [3] Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
authors.affiliation: 1] Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [2] Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. [3] Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000666:Amphotericin B / Q000737:chemistry*; D000935:Antifungal Agents / Q000737:chemistry*; D008051:Lipid Bilayers; D009682:Magnetic Resonance Spectroscopy; D010539:Permeability; D013261:Sterols / Q000737:chemistry*
chemical_list: D000935:Antifungal Agents; D008051:Lipid Bilayers; D013261:Sterols; D000666:Amphotericin B