Carbene formation as a mechanism for efficient intracellular uptake of cationic antimicrobial carbon acid polymers
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.
Authors
- Yunn‐Hwen Gan (ORCID: https://orcid.org/0000-0001-9881-6881)
- Zhi Yuan Kok (ORCID: https://orcid.org/0009-0009-6598-426X)
- Aoxin Guo (ORCID: https://orcid.org/0000-0002-7072-4106)
- Sumod A. Pullarkat (ORCID: https://orcid.org/0000-0002-4150-2408)
- Richard D. Webster (ORCID: https://orcid.org/0000-0002-0896-1960)
- Shucheng Tan (ORCID: https://orcid.org/0000-0001-8534-7422)
- Panyawut Tonanon (ORCID: https://orcid.org/0000-0002-8148-4216)
- Guangmin Wei (ORCID: https://orcid.org/0000-0001-7710-122X)
- Tram T. Dang (ORCID: https://orcid.org/0000-0001-6464-0101)
- M. Panneerselvam
- Madhu Babu Tatina (ORCID: https://orcid.org/0000-0003-3495-1800)
- Ying Jie Ooi (ORCID: https://orcid.org/0000-0002-2742-2516)
- Justin Tze Yang Ng (ORCID: https://orcid.org/0000-0003-2448-3628)
- Yonggui Robin (ORCID: https://orcid.org/0000-0003-0573-257X)
- Chong Hui Koh (ORCID: https://orcid.org/0000-0002-7726-0041)
- Kaixi Zhang (ORCID: https://orcid.org/0009-0003-0317-7629)
- Paula T. Hammond (ORCID: https://orcid.org/0000-0002-9835-192X)
- Yuguang Mu (ORCID: https://orcid.org/0000-0002-2499-026X)
- Mary Bee Eng Chan‐Park (ORCID: https://orcid.org/0000-0003-3761-7517)
- Mallikharjuna Rao Lambu
- Angelika Gründling (ORCID: https://orcid.org/0000-0002-6235-8687)
- E. Peter Greenberg (ORCID: https://orcid.org/0000-0001-9474-8041)
- Kévin Pethe (ORCID: https://orcid.org/0000-0003-0916-8873)
- Zheng Wang (ORCID: https://orcid.org/0000-0001-7678-0072)
- Qingjie Li (ORCID: https://orcid.org/0000-0003-1805-670X)
- Chongyun Tan (ORCID: https://orcid.org/0009-0004-1994-3380)
- Quang Huy Nhat Vu (ORCID: https://orcid.org/0009-0008-0818-981X)
Institutions
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- University of Washington (US)
- Water Research Institute (SK)
- Singapore Institute for Clinical Sciences (SG)
- Institute of Bioengineering and Nanotechnology (SG)
- The Affiliated Hospital to Changchun University of Chinese Medicine (CN)
- Singapore Centre for Environmental Life Sciences Engineering (SG)
- National Centre for Infectious Diseases (SG)
- Singapore-MIT Alliance for Research and Technology (SG)
- Imperial College London (GB)
- Massachusetts Institute of Technology (US)
- Singapore Management University (SG)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-12
- DOI
- https://doi.org/10.1038/s41467-025-61724-y
- Citations
- 5
- Primary Topic
- Antimicrobial agents and applications
- Type
- article
- Field-Weighted Citation Impact
- 4.68
Funders
- Wellcome Trust
- Ministry of Education - Singapore
- Ministry of Education, India
- Bộ Giáo dục và Ðào tạo