Ribosomally derived lipopeptides containing distinct fatty acyl moieties

• Published in: Proceedings of the National Academy of Sciences
• Main Authors: Hubrich, Florian, Bösch, Nina, Chepkirui, Clara, Morinaka, Brandon, Rust, Michael, Gugger, Muriel, Robinson, Serina, Vagstad, Anna, Piel, Jörn
• Other Authors: Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology Zürich (ETH Zürich), National University of Singapore (NUS), Collection des Cyanobactéries, Institut Pasteur Paris (IP)-Université Paris Cité (UPCité), Swiss Federal Insitute of Aquatic Science and Technology Dübendorf (EAWAG), We are grateful for financial support (F.H. for financial support by the Vontobel Foundation, S.L.R. for financial support by the ETH Zürich Postdoctoral Fellowship 20-1 FEL-07 , and J.P. for financial support by the Swiss National Science Foundation (SNSF) National Research Program 72 “Antimicrobial resistance,” 407240_167051 ).
• Format: Article in Journal/Newspaper
• Language: English
• Published: HAL CCSD 2022
• Subjects: RiPPs; natural products; peptides; N-acylation; biosynthesis; [SDV]Life Sciences [q-bio]; Arctic; Arctic Ocean
• Online Access: https://hal-pasteur.archives-ouvertes.fr/pasteur-03526529; https://hal-pasteur.archives-ouvertes.fr/pasteur-03526529/document; https://hal-pasteur.archives-ouvertes.fr/pasteur-03526529/file/e2113120119.full.pdf; https://doi.org/10.1073/pnas.2113120119

International audience Lipopeptides represent a large group of microbial natural products that include important antibacterial and antifungal drugs and some of the most-powerful known biosurfactants. The vast majority of lipopeptides comprise cyclic peptide backbones N-terminally equipped with various fatty acyl moieties. The known compounds of this type are biosynthesized by nonribosomal peptide synthetases, giant enzyme complexes that assemble their products in a non–gene-encoded manner. Here, we report the genome-guided discovery of ribosomally derived, fatty-acylated lipopeptides, termed selidamides. Heterologous reconstitution of three pathways, two from cyanobacteria and one from an arctic, ocean-derived alphaproteobacterium, allowed structural characterization of the probable natural products and suggest that selidamides are widespread over various bacterial phyla. The identified representatives feature cyclic peptide moieties and fatty acyl units attached to (hydroxy)ornithine or lysine side chains by maturases of the GCN5-related N -acetyltransferase superfamily. In contrast to nonribosomal lipopeptides that are usually produced as congener mixtures, the three selidamides are selectively fatty acylated with C 10 , C 12 , or C 16 fatty acids, respectively. These results highlight the ability of ribosomal pathways to emulate products with diverse, nonribosomal-like features and add to the biocatalytic toolbox for peptide drug improvement and targeted discovery.