Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers
Abstract Cationic polymers have emerged as promising next-generation antimicrobial agents, albeit with inherent limitations such as low potency and limited biocompatibility. Classical cationic polymers kill bacteria via physical membrane disruption. We propose a non-classical mechanism of crossing t...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61724-y |
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| author | Chong Hui Koh Mallikharjuna Rao Lambu Chongyun Tan Guangmin Wei Zhi Yuan Kok Kaixi Zhang Quang Huy Nhat Vu Muthuvel Panneerselvam Ying Jie Ooi Shiow Han Tan Zheng Wang Madhu Babu Tatina Justin Tze Yang Ng Aoxin Guo Panyawut Tonanon Tram T. Dang Yunn-Hwen Gan Yuguang Mu Paula T. Hammond Yonggui Robin Chi Richard D. Webster Sumod A. Pullarkat Qingjie Li E. Peter Greenberg Angelika Gründling Kevin Pethe Mary B. Chan-Park |
| author_facet | Chong Hui Koh Mallikharjuna Rao Lambu Chongyun Tan Guangmin Wei Zhi Yuan Kok Kaixi Zhang Quang Huy Nhat Vu Muthuvel Panneerselvam Ying Jie Ooi Shiow Han Tan Zheng Wang Madhu Babu Tatina Justin Tze Yang Ng Aoxin Guo Panyawut Tonanon Tram T. Dang Yunn-Hwen Gan Yuguang Mu Paula T. Hammond Yonggui Robin Chi Richard D. Webster Sumod A. Pullarkat Qingjie Li E. Peter Greenberg Angelika Gründling Kevin Pethe Mary B. Chan-Park |
| author_sort | Chong Hui Koh |
| collection | DOAJ |
| description | Abstract Cationic polymers have emerged as promising next-generation antimicrobial agents, albeit with inherent limitations such as low potency and limited biocompatibility. Classical cationic polymers kill bacteria via physical membrane disruption. We propose a non-classical mechanism of crossing the bacterial plasma membrane barrier, a step required for subsequent inhibition of intracellular targets, by cationic polymers which are carbon acids. Oligoimidazolium (OIM) carbon acids, instead of lysing bacteria, transiently deprotonate in water to form hydrophobic N-heterocyclic carbenes (NHCs) and exhibit efficient plasma membrane translocation. Only OIMs that are carbon acids have potent antibacterial activities against even colistin- and multidrug-resistant bacteria. OIM amide derivatives exhibit excellent antibacterial efficacy in murine sepsis and thigh infection models, while a polymeric version acts as a prophylactic agent against bovine mastitis, which is a global agricultural problem. This study unveils a promising path for the development of an alternative class of potent antimicrobial agents. |
| format | Article |
| id | doaj-art-bf4fc0c09bdc4183aeffcbfcdabe425e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bf4fc0c09bdc4183aeffcbfcdabe425e2025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-61724-yCarbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymersChong Hui Koh0Mallikharjuna Rao Lambu1Chongyun Tan2Guangmin Wei3Zhi Yuan Kok4Kaixi Zhang5Quang Huy Nhat Vu6Muthuvel Panneerselvam7Ying Jie Ooi8Shiow Han Tan9Zheng Wang10Madhu Babu Tatina11Justin Tze Yang Ng12Aoxin Guo13Panyawut Tonanon14Tram T. Dang15Yunn-Hwen Gan16Yuguang Mu17Paula T. Hammond18Yonggui Robin Chi19Richard D. Webster20Sumod A. Pullarkat21Qingjie Li22E. Peter Greenberg23Angelika Gründling24Kevin Pethe25Mary B. Chan-Park26School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Biological Sciences, NTUSchool of Biological Sciences, NTUSchool of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)Infectious Diseases Translational Research Program, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS)School of Biological Sciences, NTUSingapore-MIT Alliance for Research and Technology (SMART)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese MedicineDepartment of Microbiology, University of Washington School of MedicineDepartment of Infectious Disease, Section of Molecular Microbiology and Centre for Bacterial Resistance Biology, Imperial College LondonCentre for Antimicrobial Bioengineering, NTUSchool of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University (NTU)Abstract Cationic polymers have emerged as promising next-generation antimicrobial agents, albeit with inherent limitations such as low potency and limited biocompatibility. Classical cationic polymers kill bacteria via physical membrane disruption. We propose a non-classical mechanism of crossing the bacterial plasma membrane barrier, a step required for subsequent inhibition of intracellular targets, by cationic polymers which are carbon acids. Oligoimidazolium (OIM) carbon acids, instead of lysing bacteria, transiently deprotonate in water to form hydrophobic N-heterocyclic carbenes (NHCs) and exhibit efficient plasma membrane translocation. Only OIMs that are carbon acids have potent antibacterial activities against even colistin- and multidrug-resistant bacteria. OIM amide derivatives exhibit excellent antibacterial efficacy in murine sepsis and thigh infection models, while a polymeric version acts as a prophylactic agent against bovine mastitis, which is a global agricultural problem. This study unveils a promising path for the development of an alternative class of potent antimicrobial agents.https://doi.org/10.1038/s41467-025-61724-y |
| spellingShingle | Chong Hui Koh Mallikharjuna Rao Lambu Chongyun Tan Guangmin Wei Zhi Yuan Kok Kaixi Zhang Quang Huy Nhat Vu Muthuvel Panneerselvam Ying Jie Ooi Shiow Han Tan Zheng Wang Madhu Babu Tatina Justin Tze Yang Ng Aoxin Guo Panyawut Tonanon Tram T. Dang Yunn-Hwen Gan Yuguang Mu Paula T. Hammond Yonggui Robin Chi Richard D. Webster Sumod A. Pullarkat Qingjie Li E. Peter Greenberg Angelika Gründling Kevin Pethe Mary B. Chan-Park Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers Nature Communications |
| title | Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| title_full | Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| title_fullStr | Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| title_full_unstemmed | Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| title_short | Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| title_sort | carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers |
| url | https://doi.org/10.1038/s41467-025-61724-y |
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