Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers
Name
s41467-025-61724-y.pdf
Description
Published version
Size
2.44 MB
Format
Adobe PDF
Checksum (MD5)
3a03f73add4617ad92390a948b4d0c62
Author(s)
Koh, Chong Hui
Lambu, Mallikharjuna Rao
Tan, Chongyun
Wei, Guangmin
Kok, Zhi Yuan
Zhang, Kaixi
Vu, Quang Huy Nhat
Panneerselvam, Muthuvel
Ooi, Ying Jie
Tan, Shiow Han
Date Issued
July 12, 2025
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Koh, C.H., Lambu, M.R., Tan, C. et al. Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers. Nat Commun 16, 6460 (2025).
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1038/s41467-025-61724-y
