Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin
Abstract Antimicrobial resistance poses a severe threat to human health, with colistin serving as a critical medication in clinical trials against multidrug-resistant Gram-negative bacteria. However, the efficacy of colistin is increasingly compromised due to the rise of MCR-positive bacteria worldw...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07911-5 |
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| _version_ | 1849390255425191936 |
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| author | Tianqi Xu Dan Fang Fulei Li Zhiqiang Wang Yuan Liu |
| author_facet | Tianqi Xu Dan Fang Fulei Li Zhiqiang Wang Yuan Liu |
| author_sort | Tianqi Xu |
| collection | DOAJ |
| description | Abstract Antimicrobial resistance poses a severe threat to human health, with colistin serving as a critical medication in clinical trials against multidrug-resistant Gram-negative bacteria. However, the efficacy of colistin is increasingly compromised due to the rise of MCR-positive bacteria worldwide. Here, we reveal a notable metabolic disparity between mcr-positive and -negative bacteria through transcriptome and metabolomics analysis. Specifically, pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, was significantly diminished in mcr-positive bacteria. Conversely, supplementing with PLP could reverse the metabolic profile of drug-resistant bacteria and effectively restore colistin’s bactericidal properties. Mechanistically, PLP was found to augment bacterial proton motive force by inhibiting the Kdp transport system, a bacterial K+ transport ATPase, thereby facilitating the binding of the positively charged colistin to the negatively charged bacterial membrane components. Furthermore, PLP supplementation triggers ferroptosis-like death by accumulating ferrous ions and inducing lipid peroxidation. These two modes of action collectively resensitize mcr-harboring Gram-negative bacteria to colistin therapy. Altogether, our study provides a novel metabolic-driven antibiotic sensitization strategy to tackle antibiotic resistance and identifies a potentially safe antibiotic synergist. |
| format | Article |
| id | doaj-art-5aea0a5896f64f5cbe0f87fdccc18f1f |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-5aea0a5896f64f5cbe0f87fdccc18f1f2025-08-20T03:41:43ZengNature PortfolioCommunications Biology2399-36422025-03-018111410.1038/s42003-025-07911-5Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistinTianqi Xu0Dan Fang1Fulei Li2Zhiqiang Wang3Yuan Liu4Jiangsu 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 Antimicrobial resistance poses a severe threat to human health, with colistin serving as a critical medication in clinical trials against multidrug-resistant Gram-negative bacteria. However, the efficacy of colistin is increasingly compromised due to the rise of MCR-positive bacteria worldwide. Here, we reveal a notable metabolic disparity between mcr-positive and -negative bacteria through transcriptome and metabolomics analysis. Specifically, pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, was significantly diminished in mcr-positive bacteria. Conversely, supplementing with PLP could reverse the metabolic profile of drug-resistant bacteria and effectively restore colistin’s bactericidal properties. Mechanistically, PLP was found to augment bacterial proton motive force by inhibiting the Kdp transport system, a bacterial K+ transport ATPase, thereby facilitating the binding of the positively charged colistin to the negatively charged bacterial membrane components. Furthermore, PLP supplementation triggers ferroptosis-like death by accumulating ferrous ions and inducing lipid peroxidation. These two modes of action collectively resensitize mcr-harboring Gram-negative bacteria to colistin therapy. Altogether, our study provides a novel metabolic-driven antibiotic sensitization strategy to tackle antibiotic resistance and identifies a potentially safe antibiotic synergist.https://doi.org/10.1038/s42003-025-07911-5 |
| spellingShingle | Tianqi Xu Dan Fang Fulei Li Zhiqiang Wang Yuan Liu Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin Communications Biology |
| title | Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin |
| title_full | Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin |
| title_fullStr | Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin |
| title_full_unstemmed | Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin |
| title_short | Vitamin B6 resensitizes mcr-carrying Gram-negative bacteria to colistin |
| title_sort | vitamin b6 resensitizes mcr carrying gram negative bacteria to colistin |
| url | https://doi.org/10.1038/s42003-025-07911-5 |
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