A post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity

Daniel S. Palacios, Thomas M. Anderson, Martin D. Burke

Research output: Contribution to journalArticlepeer-review

Abstract

The clinically vital antimycotic agent amphotericin B represents the archetypal example of a channel-forming small molecule. The leading model for self-assembly of the amphotericin B channel predicts that the C(41) carboxylate and the C(3′) ammonium ions form intermolecular salt bridges/hydrogen bonds that are critical for stability. We herein report a flexible degradative synthesis pathway that enables the removal of either or both of these groups from amphotericin B. We further demonstrate with extensive NMR experiments that deleting these groups does not alter the conformation of the polyene macrolide skeleton. As predicted by the leading model, amphotericin B derivatives lacking the mycosamine sugar that contains the C(3′) ammonium ion are completely inactive against Saccharomyces cerevisiae. However, strikingly-and in strong contradiction with the current model-the amphotericin B derivative lacking the C(41) carboxylate is at least equipotent to the natural product. Collectively, these findings demonstrate that the leading model for the mechanism of action of amphotericin B must be significantly revised-either the C(41) carboxylate is not required for channel formation or channel formation is not required for antifungal activity.

Original languageEnglish (US)
Pages (from-to)13804-13805
Number of pages2
JournalJournal of the American Chemical Society
Volume129
Issue number45
DOIs
StatePublished - Nov 14 2007

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint

Dive into the research topics of 'A post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity'. Together they form a unique fingerprint.

Cite this