Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers

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 () and Mary B. Chan-Park ()
Additional contact information
Chong Hui Koh: Nanyang Technological University (NTU)
Mallikharjuna Rao Lambu: Nanyang Technological University (NTU)
Chongyun Tan: Nanyang Technological University (NTU)
Guangmin Wei: Nanyang Technological University (NTU)
Zhi Yuan Kok: Nanyang Technological University (NTU)
Kaixi Zhang: Nanyang Technological University (NTU)
Quang Huy Nhat Vu: Nanyang Technological University (NTU)
Muthuvel Panneerselvam: Nanyang Technological University (NTU)
Ying Jie Ooi: Nanyang Technological University (NTU)
Shiow Han Tan: Nanyang Technological University (NTU)
Zheng Wang: Nanyang Technological University (NTU)
Madhu Babu Tatina: Nanyang Technological University (NTU)
Justin Tze Yang Ng: NTU
Aoxin Guo: NTU
Panyawut Tonanon: Nanyang Technological University (NTU)
Tram T. Dang: Nanyang Technological University (NTU)
Yunn-Hwen Gan: National University of Singapore (NUS)
Yuguang Mu: NTU
Paula T. Hammond: Singapore-MIT Alliance for Research and Technology (SMART)
Yonggui Robin Chi: Nanyang Technological University (NTU)
Richard D. Webster: Nanyang Technological University (NTU)
Sumod A. Pullarkat: Nanyang Technological University (NTU)
Qingjie Li: The Affiliated Hospital to Changchun University of Chinese Medicine
E. Peter Greenberg: University of Washington School of Medicine
Angelika Gründling: Imperial College London
Kevin Pethe: NTU
Mary B. Chan-Park: Nanyang Technological University (NTU)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61724-y

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