Exploring RiPP-derived N-acyltransferases for genetically encoded lipopeptide engineering
- 1Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Vladimir-Prelog-Weg 4 8093 Zürich Switzerland
Abstract
Lipopeptides possess diverse bioactivities with widespread uses as antimicrobial drugs and biosurfactants but their biosynthetic engineering remains challenging. Classical lipopeptides (such as daptomycin or surfactin) are biosynthesized by modular, non-ribosomal megasynthetases. An alternative streamlined route to lipopeptides are the ribosomally synthesized and post-translationally modified peptides (RiPPs) derived from gene-encoded precursor proteins. We recently characterized a novel class of post-translational modification enzymes in RiPPs that catalyze fatty acylation of ornithine and lysine side chains. The resulting lipopeptides were termed selidamides. To assess the use of selidamide N-acyltransferases as biocatalysts, we probed the peptide substrate specificity of the model lauroyl-transferase KspN from kamptornamide biosynthesis. Nearest-neighbor, lysine-scan, and truncation mutants demonstrated promiscuity for the peptide substrate. As a proof-of-concept toward designer lipopeptides using RiPP biosynthetic principles, we produced sequences mimicking bioactive non-ribosomal lipopeptides and tested their conversion by maturases from the kamptornamide biosynthetic pathway. Ornithines, fatty acyl groups, and lanthionine macrocycles were installed in the mimics as a promising start toward the directed biosynthesis of custom lipopeptides.
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BibTeX
@article{bosch2026exploring,
title = {{Exploring RiPP-derived N-acyltransferases for genetically encoded lipopeptide engineering}},
author = {Nina M. Bösch and Manon Coste and Johannes A. Rudmann Eckert and Gabriel Cervera Arriaga and Annina R. Meyer and Eléonore Moore and Daniel Richter and Jörn Piel and Anna L. Vagstad},
journal = {RSC Chemical Biology},
year = {2026},
month = oct,
doi = {10.1039/d6cb00169f},
url = {https://doi.org/10.1039/d6cb00169f},
note = {CC BY-NC 3.0},
}
RIS
TY - JOUR
TI - Exploring RiPP-derived N-acyltransferases for genetically encoded lipopeptide engineering
AU - Nina M. Bösch
AU - Manon Coste
AU - Johannes A. Rudmann Eckert
AU - Gabriel Cervera Arriaga
AU - Annina R. Meyer
AU - Eléonore Moore
AU - Daniel Richter
AU - Jörn Piel
AU - Anna L. Vagstad
PY - 2026
DA - 2026/10/06
JO - RSC Chemical Biology
DO - 10.1039/d6cb00169f
UR - https://doi.org/10.1039/d6cb00169f
AB - Lipopeptides possess diverse bioactivities with widespread uses as antimicrobial drugs and biosurfactants but their biosynthetic engineering remains challenging. Classical lipopeptides (such as daptomycin or surfactin) are biosynthesized by modular, non-ribosomal megasynthetases. An alternative streamlined route to lipopeptides are the ribosomally synthesized and post-translationally modified peptides (RiPPs) derived from gene-encoded precursor proteins. We recently characterized a novel class of post-translational modification enzymes in RiPPs that catalyze fatty acylation of ornithine and lysine side chains. The resulting lipopeptides were termed selidamides. To assess the use of selidamide N-acyltransferases as biocatalysts, we probed the peptide substrate specificity of the model lauroyl-transferase KspN from kamptornamide biosynthesis. Nearest-neighbor, lysine-scan, and truncation mutants demonstrated promiscuity for the peptide substrate. As a proof-of-concept toward designer lipopeptides using RiPP biosynthetic principles, we produced sequences mimicking bioactive non-ribosomal lipopeptides and tested their conversion by maturases from the kamptornamide biosynthetic pathway. Ornithines, fatty acyl groups, and lanthionine macrocycles were installed in the mimics as a promising start toward the directed biosynthesis of custom lipopeptides.
SN - 2633-0679
ER -