Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides

Xiaorui Guo, Jiabao Zhang, Xinyi Li, Emily Xiao, Justin D. Lange, Chad M. Rienstra, Martin D. Burke, Douglas A. Mitchell

Research output: Contribution to journalArticlepeer-review


Amphotericin-like glycosylated polyene macrolides (GPMs) are a clinically and industrially important family of natural products, but the mechanisms by which they exert their extraordinary biological activities have remained unclear for more than half a century. Amphotericin B exerts fungicidal action primarily via self-assembly into an extramembranous sponge that rapidly extracts ergosterol from fungal membranes, but it has remained unclear whether this mechanism is applicable to other GPMs. Using a highly conserved polyene-hemiketal region of GPMs that we hypothesized to represent a conserved ergosterol-binding domain, we bioinformatically mapped the entirety of the GPM sequence-function space and expanded the number of GPM biosynthetic gene clusters (BGCs) by 10-fold. We further leveraged bioinformatic predictions and tetrazine-based reactivity screening targeting the electron-rich polyene region of GPMs to discover a first-in-class methyltetraene-and diepoxide-containing GPM, kineosporicin, and to assign BGCs to many new producers of previously reported members. Leveraging a range of structurally diverse known and newly discovered GPMs, we found that the sterol sponge mechanism of fungicidal action is conserved.

Original languageEnglish (US)
Pages (from-to)781-791
Number of pages11
JournalACS Central Science
Issue number5
StatePublished - May 26 2021

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering


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