Enzymatic glycosylation and amidation reshapes polyene bioactivity
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Fungal diseases are an escalating threat to human health, driven by rising antimicrobial resistance and a lack of new antifungal treatments1,2. Polyenes, a class of complex natural products, have been widely used as antifungal agents due to their broad-spectrum activity3. However, their clinical use is limited by severe toxicity and poor solubility, making safer and more effective alternatives urgently needed4. Previous efforts to generate improved polyenes have relied on costly, step-inefficient and atom-inefficient chemical syntheses5,6. Here we describe the discovery and characterization of pathways to previously undescribed polyenes, including unusual glycosyltransferase enzymes that introduce sugars onto polyene scaffolds. We also show how the reaction scope of an amidotransferase enzyme can be expanded to transform the detrimental carboxylate substituent of polyenes to alternative functionality. Introduction of a second sugar combined with carboxylate modifications leads to more potent polyene antifungals, with reduced toxicity, that are accessible by clean and efficient fermentation or enzymatic routes.
Date Issued
2026-07-29
Date Acceptance
2026-06-22
Citation
Nature, 2026
ISSN
0028-0836
Publisher
Nature Research
Journal / Book Title
Nature
Copyright Statement
© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41586-026-10834-8
Publication Status
Published online
Date Publish Online
2026-07-29