Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens
Abstract Menaquinone (MK) in bacterial membrane is an attractive target for the development of novel therapeutic agents. Mining the untapped chemical diversity encoded by Gram-negative bacteria presents an opportunity to identify additional MK-binding antibiotics (MBAs). By MK-binding motif searchin...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07159-5 |
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| author | Runze Sun Di Zhao Xuchang Yu Fei Zhang Ruixiang You Xiaoxia Luo Lei Li |
| author_facet | Runze Sun Di Zhao Xuchang Yu Fei Zhang Ruixiang You Xiaoxia Luo Lei Li |
| author_sort | Runze Sun |
| collection | DOAJ |
| description | Abstract Menaquinone (MK) in bacterial membrane is an attractive target for the development of novel therapeutic agents. Mining the untapped chemical diversity encoded by Gram-negative bacteria presents an opportunity to identify additional MK-binding antibiotics (MBAs). By MK-binding motif searching of bioinformatically predicted linear non-ribosomal peptides from 14,298 sequenced genomes of 45 underexplored Gram-negative bacterial genera, here we identify a novel MBA structural family, including silvmeb and pseudomeb, using structure prediction-guided chemical synthesis. Both MBAs show rapid bacteriolysis by MK-dependent membrane depolarization to achieve their potent activities against a panel of Gram-positive pathogens. Furthermore, both MBAs are proven to be effective against methicillin-resistant Staphylococcus aureus in a murine peritonitis-sepsis model. Our findings suggest that MBAs are a kind of structurally diverse and still underexplored antibacterial lipodepsipeptide class. The interrogation of underexplored bacterial taxa using synthetic bioinformatic natural product methods is an appealing strategy for discovering novel biomedically relevant agents to confront the crisis of antimicrobial resistance. |
| format | Article |
| id | doaj-art-3416cd9444ec4cebba444218fedc2316 |
| institution | DOAJ |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-3416cd9444ec4cebba444218fedc23162025-08-20T02:50:08ZengNature PortfolioCommunications Biology2399-36422024-11-01711910.1038/s42003-024-07159-5Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogensRunze Sun0Di Zhao1Xuchang Yu2Fei Zhang3Ruixiang You4Xiaoxia Luo5Lei Li6State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityCollege of Life Science, Tarim UniversityState Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong UniversityAbstract Menaquinone (MK) in bacterial membrane is an attractive target for the development of novel therapeutic agents. Mining the untapped chemical diversity encoded by Gram-negative bacteria presents an opportunity to identify additional MK-binding antibiotics (MBAs). By MK-binding motif searching of bioinformatically predicted linear non-ribosomal peptides from 14,298 sequenced genomes of 45 underexplored Gram-negative bacterial genera, here we identify a novel MBA structural family, including silvmeb and pseudomeb, using structure prediction-guided chemical synthesis. Both MBAs show rapid bacteriolysis by MK-dependent membrane depolarization to achieve their potent activities against a panel of Gram-positive pathogens. Furthermore, both MBAs are proven to be effective against methicillin-resistant Staphylococcus aureus in a murine peritonitis-sepsis model. Our findings suggest that MBAs are a kind of structurally diverse and still underexplored antibacterial lipodepsipeptide class. The interrogation of underexplored bacterial taxa using synthetic bioinformatic natural product methods is an appealing strategy for discovering novel biomedically relevant agents to confront the crisis of antimicrobial resistance.https://doi.org/10.1038/s42003-024-07159-5 |
| spellingShingle | Runze Sun Di Zhao Xuchang Yu Fei Zhang Ruixiang You Xiaoxia Luo Lei Li Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens Communications Biology |
| title | Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens |
| title_full | Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens |
| title_fullStr | Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens |
| title_full_unstemmed | Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens |
| title_short | Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens |
| title_sort | discovery of a family of menaquinone targeting cyclic lipodepsipeptides for multidrug resistant gram positive pathogens |
| url | https://doi.org/10.1038/s42003-024-07159-5 |
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