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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月12日

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  • 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

摘要

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.