Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes

Agnieszka Lewandowska, Corinne P. Soutar, Alexander I. Greenwood, Evgeny Nimerovsky, Ashley M. De Lio, Jordan T. Holler, Grant S. Hisao, Anuj Khandelwal, Jiabao Zhang, Anna M. SantaMaria, Charles D. Schwieters, Taras V. Pogorelov, Martin Burke, Chad Rienstra

Research output: Contribution to journalArticlepeer-review


Amphotericin B (AmB) is a powerful but toxic fungicide that operates via enigmatic small molecule–small molecule interactions. This mechanism has challenged the frontiers of structural biology for half a century. We recently showed AmB primarily forms extramembranous aggregates that kill yeast by extracting ergosterol from membranes. Here, we report key structural features of these antifungal ‘sponges’ illuminated by high-resolution magic-angle spinning solid-state NMR, in concert with simulated annealing and molecular dynamics computations. The minimal unit of assembly is an asymmetric head-to-tail homodimer: one molecule adopts an all-trans C1–C13 motif, the other a C6–C7-gauche conformation. These homodimers are staggered in a clathrate-like lattice with large void volumes similar to the size of sterols. These results illuminate the atomistic interactions that underlie fungicidal assemblies of AmB and suggest this natural product may form biologically active clathrates that host sterol guests.

Original languageEnglish (US)
Pages (from-to)972-981
Number of pages10
JournalNature Structural Biology
Issue number12
StatePublished - Dec 2021


  • Drug discovery
  • Supramolecular assembly
  • Solid-state NMR

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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