Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance
Abstract Tigecycline is a last-resort antibiotic to treat complicated infections caused by multidrug-resistant pathogens, while the emergence of plasmid-mediated tet(X) family severely compromises its clinical efficacy. Novel antimicrobial strategies not limited to new antibiotics in pharmaceutical...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55791-w |
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| author | Dan Fang Tianqi Xu Fulei Li Yue Sun Jingyi Sun Yanqing Yin Haijie Zhang Zhiqiang Wang Yuan Liu |
| author_facet | Dan Fang Tianqi Xu Fulei Li Yue Sun Jingyi Sun Yanqing Yin Haijie Zhang Zhiqiang Wang Yuan Liu |
| author_sort | Dan Fang |
| collection | DOAJ |
| description | Abstract Tigecycline is a last-resort antibiotic to treat complicated infections caused by multidrug-resistant pathogens, while the emergence of plasmid-mediated tet(X) family severely compromises its clinical efficacy. Novel antimicrobial strategies not limited to new antibiotics in pharmaceutical pipeline are urgently needed. Herein, we reveal the metabolic disparities between tet(X)-negative and -positive E. coli, including distinct energy demand patterns under tigecycline exposure. In particular, the cysteine and methionine metabolism pathway is remarkably downregulated in tet(X)-positive bacteria. More importantly, we find that the addition of exogenous L-methionine (Met) effectively resensitizes tet(X)-positive pathogens to tigecycline. Our mechanistic analysis demonstrates that exogenous Met promotes intracellular tigecycline accumulation by upregulating bacterial proton motive force. Moreover, Met accelerates the conversion to S-adenosyl-L-methionine, an essential methyl donor, thereby enhancing 5mC methylation modification in the promoter region of tet(X4) gene and reducing its expression. Consistently, the potentiation of Met to tigecycline is abolished in tet(X4)-carrying E. coli Δdcm but restored in dcm-complementary bacteria, which encodes DNA-cytosine methyltransferase. In multiple animal models of infection, Met markedly potentiates the effectiveness of tigecycline against pathogenic E. coli and K. pneumoniae. Overall, this work highlights the therapeutic potential of Met in overcoming plasmid-mediated high-level tigecycline resistance, and provides a new paradigm to enhance antibiotic efficacy by harnessing cellular metabolic networks as well as epigenetic modifications. |
| format | Article |
| id | doaj-art-ec7c2549dd99405ca4ad427c372d8901 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ec7c2549dd99405ca4ad427c372d89012025-01-12T12:31:46ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55791-wMethionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistanceDan Fang0Tianqi Xu1Fulei Li2Yue Sun3Jingyi Sun4Yanqing Yin5Haijie Zhang6Zhiqiang Wang7Yuan Liu8Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityJiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou UniversityAbstract Tigecycline is a last-resort antibiotic to treat complicated infections caused by multidrug-resistant pathogens, while the emergence of plasmid-mediated tet(X) family severely compromises its clinical efficacy. Novel antimicrobial strategies not limited to new antibiotics in pharmaceutical pipeline are urgently needed. Herein, we reveal the metabolic disparities between tet(X)-negative and -positive E. coli, including distinct energy demand patterns under tigecycline exposure. In particular, the cysteine and methionine metabolism pathway is remarkably downregulated in tet(X)-positive bacteria. More importantly, we find that the addition of exogenous L-methionine (Met) effectively resensitizes tet(X)-positive pathogens to tigecycline. Our mechanistic analysis demonstrates that exogenous Met promotes intracellular tigecycline accumulation by upregulating bacterial proton motive force. Moreover, Met accelerates the conversion to S-adenosyl-L-methionine, an essential methyl donor, thereby enhancing 5mC methylation modification in the promoter region of tet(X4) gene and reducing its expression. Consistently, the potentiation of Met to tigecycline is abolished in tet(X4)-carrying E. coli Δdcm but restored in dcm-complementary bacteria, which encodes DNA-cytosine methyltransferase. In multiple animal models of infection, Met markedly potentiates the effectiveness of tigecycline against pathogenic E. coli and K. pneumoniae. Overall, this work highlights the therapeutic potential of Met in overcoming plasmid-mediated high-level tigecycline resistance, and provides a new paradigm to enhance antibiotic efficacy by harnessing cellular metabolic networks as well as epigenetic modifications.https://doi.org/10.1038/s41467-024-55791-w |
| spellingShingle | Dan Fang Tianqi Xu Fulei Li Yue Sun Jingyi Sun Yanqing Yin Haijie Zhang Zhiqiang Wang Yuan Liu Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance Nature Communications |
| title | Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance |
| title_full | Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance |
| title_fullStr | Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance |
| title_full_unstemmed | Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance |
| title_short | Methionine-driven methylation modification overcomes plasmid-mediated high-level tigecycline resistance |
| title_sort | methionine driven methylation modification overcomes plasmid mediated high level tigecycline resistance |
| url | https://doi.org/10.1038/s41467-024-55791-w |
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