Hydroxyl-Terminated Ester-Containing OIM Carbon Acid Nanoparticle with Low Cytotoxicity Rescues Mice from Resistant Acinetobacter baumannii Infections

Abstract Antimicrobial resistance is a global public health threat. Cationic polymers are a potential alternative class of antimicrobial agents, but their bacteria-killing efficacy and long-term organ biosafety are often insufficient for clinical translation. Herein, we optimize the degradable linkers and terminals of oligoimidazolium (OIM) carbon acids to improve their efficacy and reduce their long-term toxicity to various organs. We found that neat OIM1-8-2E-OH (VI) made with hydroxyl terminals (−OH) and gamma ester linkers (E) exhibits enhanced antibacterial properties while achieving markedly improved in vitro biosafety that potentially reduces in vivo (long-term) liver/kidney metabolism toxicity. To further avoid in vivo (short-term) blood coagulation toxicity commonly associated with cationic agents, we encapsulated neat (VI) in a chitosan-based matrix (CS-DA) derived from chitosan (CS) and 2,3-dimethyl maleic anhydride (DA) grafts. The matrix of the resultant nanoparticle (NP) degrades at acidic infection sites to expose the intact and potent (VI), but shields the positive charges of the neat OIM while in systemic circulation, thereby mitigating acute in vivo toxicity due to blood coagulation. (VI)’s gamma-ester linkages degrade at physiological pH to reduce organ toxicity but are stable at acidic infection sites. In three murine infection models with carbapenem-resistant Acinetobacter baumannii, the (VI)-NP reduces the bacterial loads by 2 to 8 orders of magnitude, resulting in 100% mice survival, and exhibits no signs of acute or long-term toxicity. These findings position the (VI)-NP complex made with advanced OIM as a promising therapeutic agent against multidrug-resistant bacteria, combining high efficacy with a favorable safety profile.