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, Richard D. Webster, Sumod A. Pullarkat, Qingjie Li, E. Peter Greenberg, Angelika Gründling, Kévin Pethe, Mary B. Chan‐Park
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. Cationic polymers conventionally kill bacteria via physical membrane disruptions. Here, the authors report the development of carbon acid cationic polymers that show potent activity against multidrug-resistant strains in murine infection models and prevent bovine mastitis, and present evidence that these polymers translocate across bacterial membrane aided by N-heterocyclic carbene.