Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides
Abstract Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43451-4 |
| _version_ | 1797414557305536512 |
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| author | Mathias H. Hansen Martina Adamek Dumitrita Iftime Daniel Petras Frauke Schuseil Stephanie Grond Evi Stegmann Max J. Cryle Nadine Ziemert |
| author_facet | Mathias H. Hansen Martina Adamek Dumitrita Iftime Daniel Petras Frauke Schuseil Stephanie Grond Evi Stegmann Max J. Cryle Nadine Ziemert |
| author_sort | Mathias H. Hansen |
| collection | DOAJ |
| description | Abstract Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid II targeting glycopeptide antibiotics (GPAs, exemplified by teicoplanin and vancomycin), which are used as last resort for the treatment of antibiotic resistant bacterial infections. Using a molecule-centred approach and computational techniques, we first predicted the nonribosomal peptide synthetase assembly line of paleomycin, the ancestral parent of lipid II targeting GPAs. Subsequently, we employed synthetic biology techniques to produce the predicted peptide and validated its antibiotic activity. We revealed the structure of paleomycin, which enabled us to address how nature morphs a peptide antibiotic scaffold through evolution. In doing so, we obtained temporal snapshots of key selection domains in nonribosomal peptide synthesis during the biosynthetic journey from ancestral, teicoplanin-like GPAs to modern GPAs such as vancomycin. Our study demonstrates the synergy of computational techniques and synthetic biology approaches enabling us to journey back in time, trace the temporal evolution of antibiotics, and revive these ancestral molecules. It also reveals the optimisation strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents. |
| first_indexed | 2024-03-09T05:35:02Z |
| format | Article |
| id | doaj.art-f33678345ca34f409dcf274d94b63533 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T05:35:02Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f33678345ca34f409dcf274d94b635332023-12-03T12:29:53ZengNature PortfolioNature Communications2041-17232023-11-0114111610.1038/s41467-023-43451-4Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptidesMathias H. Hansen0Martina Adamek1Dumitrita Iftime2Daniel Petras3Frauke Schuseil4Stephanie Grond5Evi Stegmann6Max J. Cryle7Nadine Ziemert8Department of Biochemistry and Molecular Biology, The Monash Biomedicine Discovery Institute, Monash UniversityInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenInstitute of Organic Chemistry, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenDepartment of Biochemistry and Molecular Biology, The Monash Biomedicine Discovery Institute, Monash UniversityInterfaculty Institute of Microbiology and Infection Medicine Tübingen, Cluster of Excellence ‘Controlling Microbes to Fight Infections’, University of TübingenAbstract Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid II targeting glycopeptide antibiotics (GPAs, exemplified by teicoplanin and vancomycin), which are used as last resort for the treatment of antibiotic resistant bacterial infections. Using a molecule-centred approach and computational techniques, we first predicted the nonribosomal peptide synthetase assembly line of paleomycin, the ancestral parent of lipid II targeting GPAs. Subsequently, we employed synthetic biology techniques to produce the predicted peptide and validated its antibiotic activity. We revealed the structure of paleomycin, which enabled us to address how nature morphs a peptide antibiotic scaffold through evolution. In doing so, we obtained temporal snapshots of key selection domains in nonribosomal peptide synthesis during the biosynthetic journey from ancestral, teicoplanin-like GPAs to modern GPAs such as vancomycin. Our study demonstrates the synergy of computational techniques and synthetic biology approaches enabling us to journey back in time, trace the temporal evolution of antibiotics, and revive these ancestral molecules. It also reveals the optimisation strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents.https://doi.org/10.1038/s41467-023-43451-4 |
| spellingShingle | Mathias H. Hansen Martina Adamek Dumitrita Iftime Daniel Petras Frauke Schuseil Stephanie Grond Evi Stegmann Max J. Cryle Nadine Ziemert Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides Nature Communications |
| title | Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides |
| title_full | Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides |
| title_fullStr | Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides |
| title_full_unstemmed | Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides |
| title_short | Resurrecting ancestral antibiotics: unveiling the origins of modern lipid II targeting glycopeptides |
| title_sort | resurrecting ancestral antibiotics unveiling the origins of modern lipid ii targeting glycopeptides |
| url | https://doi.org/10.1038/s41467-023-43451-4 |
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