Amphotericin primarily kills yeast by simply binding ergosterol

Kaitlyn C. Gray, Daniel S. Palacios, Ian Dailey, Matthew M. Endo, Brice E. Uno, Brandon C. Wilcock, Martin D. Burke

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2234-2239
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number7
DOIs
StatePublished - Feb 14 2012

Keywords

  • N-methyliminodiacetic acid boronates
  • Protein-like functions
  • Small molecules

ASJC Scopus subject areas

  • General

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