A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery
Abstract Emerging global challenges, such as antimicrobial resistance, have shifted the focus of natural product discovery from well-characterized microbial producers to underexplored taxonomic groups. Here, we computationally and experimentally characterize the biosynthetic potential of the genus P...
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Nature Portfolio
2025-06-01
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| Online Access: | https://doi.org/10.1038/s41598-025-03955-z |
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| author | Yang Liu Luis Linares-Otoya Christian Kersten Michael Marner Sanja Mihajlovic Mohamed H. Abdeldayem Sandra Semmler Molly C. Bletz Miguel Vences Marius Spohn Celine M. Zumkeller Till F. Schäberle |
| author_facet | Yang Liu Luis Linares-Otoya Christian Kersten Michael Marner Sanja Mihajlovic Mohamed H. Abdeldayem Sandra Semmler Molly C. Bletz Miguel Vences Marius Spohn Celine M. Zumkeller Till F. Schäberle |
| author_sort | Yang Liu |
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| description | Abstract Emerging global challenges, such as antimicrobial resistance, have shifted the focus of natural product discovery from well-characterized microbial producers to underexplored taxonomic groups. Here, we computationally and experimentally characterize the biosynthetic potential of the genus Pedobacter, a Bacteroidota taxon known for antibiotic production that harbors numerous uncharacterized secondary metabolite (SM)-encoding biosynthetic gene clusters (BGCs). Through phylogenomic analysis of the genus Pedobacter, we identify a distinct clade enriched in lipopeptide-associated BGCs, most of which lack known chemical products. By developing de novo genetic tools and integrating metabolomics, we linked specific secondary metabolites to their corresponding BGCs. Using synthetic and analytical chemistry as proof of concept, we isolated and structurally characterized twelve linear lipopeptides (cryopeptins A–N), containing rare dehydrovalines from Pedobacter cryoconitis PAMC 27485. We demonstrate that all cryopeptins, despite their structural heterogeneity, are biosynthesized by a single multi-domain non-ribosomal peptide synthetase (NRPS) gene cluster. Mechanistically, we propose that this BGC drives chemical diversity through combinatorial fatty acid incorporation and iterative amino acid assembly, resulting in variable peptide chain lengths. This work highlights the biosynthetic versatility of Pedobacter and outlines methods for genetic manipulation in this genus to systematically access its cryptic natural product repertoire. |
| format | Article |
| id | doaj-art-d07edaa54b584fc4bf55eeccf2e03f89 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-d07edaa54b584fc4bf55eeccf2e03f892025-08-20T02:10:32ZengNature PortfolioScientific Reports2045-23222025-06-0115111210.1038/s41598-025-03955-zA genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discoveryYang Liu0Luis Linares-Otoya1Christian Kersten2Michael Marner3Sanja Mihajlovic4Mohamed H. Abdeldayem5Sandra Semmler6Molly C. Bletz7Miguel Vences8Marius Spohn9Celine M. Zumkeller10Till F. Schäberle11Institute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenInstitute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenInstitute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University MainzInstitute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenNatural Product Department, Fraunhofer-Institute for Molecular Biology and Applied Ecology (IME-BR)Institute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenNatural Product Department, Fraunhofer-Institute for Molecular Biology and Applied Ecology (IME-BR)Department of Environmental Conservation, University of Massachusetts AmherstZoological Institute, Technische Universität BraunschweigInstitute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenInstitute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenInstitute for Insect Biotechnology with Focus on Natural Product Research, Justus- Liebig-University GiessenAbstract Emerging global challenges, such as antimicrobial resistance, have shifted the focus of natural product discovery from well-characterized microbial producers to underexplored taxonomic groups. Here, we computationally and experimentally characterize the biosynthetic potential of the genus Pedobacter, a Bacteroidota taxon known for antibiotic production that harbors numerous uncharacterized secondary metabolite (SM)-encoding biosynthetic gene clusters (BGCs). Through phylogenomic analysis of the genus Pedobacter, we identify a distinct clade enriched in lipopeptide-associated BGCs, most of which lack known chemical products. By developing de novo genetic tools and integrating metabolomics, we linked specific secondary metabolites to their corresponding BGCs. Using synthetic and analytical chemistry as proof of concept, we isolated and structurally characterized twelve linear lipopeptides (cryopeptins A–N), containing rare dehydrovalines from Pedobacter cryoconitis PAMC 27485. We demonstrate that all cryopeptins, despite their structural heterogeneity, are biosynthesized by a single multi-domain non-ribosomal peptide synthetase (NRPS) gene cluster. Mechanistically, we propose that this BGC drives chemical diversity through combinatorial fatty acid incorporation and iterative amino acid assembly, resulting in variable peptide chain lengths. This work highlights the biosynthetic versatility of Pedobacter and outlines methods for genetic manipulation in this genus to systematically access its cryptic natural product repertoire.https://doi.org/10.1038/s41598-025-03955-zBacteroidotaLipopeptidesNatural productsNRPSPedobacterBiosynthetic gene clusters (BGCs) |
| spellingShingle | Yang Liu Luis Linares-Otoya Christian Kersten Michael Marner Sanja Mihajlovic Mohamed H. Abdeldayem Sandra Semmler Molly C. Bletz Miguel Vences Marius Spohn Celine M. Zumkeller Till F. Schäberle A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery Scientific Reports Bacteroidota Lipopeptides Natural products NRPS Pedobacter Biosynthetic gene clusters (BGCs) |
| title | A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery |
| title_full | A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery |
| title_fullStr | A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery |
| title_full_unstemmed | A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery |
| title_short | A genetically tractable branch of environmental Pedobacter from the phylum Bacteroidota represents a hotspot for natural product discovery |
| title_sort | genetically tractable branch of environmental pedobacter from the phylum bacteroidota represents a hotspot for natural product discovery |
| topic | Bacteroidota Lipopeptides Natural products NRPS Pedobacter Biosynthetic gene clusters (BGCs) |
| url | https://doi.org/10.1038/s41598-025-03955-z |
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