Formulation of Stable Cationic Oligoimidazoliums for Selective Antibacterial Activity in Lung Infection

Antimicrobial peptides (AMPs) are promising alternative agents to combat the escalating antimicrobial resistance (AMR) crisis, yet their application is often limited by inherent toxicity and suboptimal performance due to poor selectivity against pathogenic bacteria. In this study, we developed a series of AMP-mimicking cationic oligoimidazoliums (OIMs), which showed structure-dependent bactericidal activities and cationic charge-associated toxicity. Specifically, among the OIMs with different degradable linkers, it was found that the OIM with a relatively stable piperazine acetamide (PzAc) linker demonstrated superior antibacterial properties but also showed in vitro and in vivo toxicities. To mitigate this issue, we employed a formulation strategy involving the electrostatic complexation of the OIM with a biodegradable anionic caging copolymer, effectively neutralizing surface charges to reduce cytotoxicity. The resulting complex nanoparticles were degraded by bacteria-secreted lipase at the infection site, thereby releasing the encapsulated OIM to target and kill the bacteria. The selective biocidal activity and enhanced safety profile of this formulation were verified with an in vivo lung infection model. This approach represents a strategy for the development of safe and effective AMP-mimicking antibacterial therapeutics.