Ethylene glycol derivative-pendanted quaternary ammonium antibacterial polymers with low cytotoxicity

Cationic poly(quaternary ammonium) (pQA) polymers exhibit excellent antibacterial efficacy but high cytotoxicity (thus low selectivity), hampering their widespread use as antibacterial agents. Herein, we systematically synthesized a series of pQA polymers (pQA-EG) containing biocompatible ethylene glycol (EG) derivative pendant groups with different chain lengths and connectivities (acyclic/cyclic). The antibacterial efficacy of pQA-EG was optimized by a moderate EG chain length, which endowed the polymer with balanced hydrophobicity/charge density. The high chain flexibility of the EG derivative combined with its good hydrophilicity was critical for significantly lowering the cytotoxicity of pQA-EG. Hence, compared with pQA polymers containing alkyl pendant groups, the pQA-EG polymer containing a long flexible EG derivative pendant group exhibited significantly lower cytotoxicity and higher selectivity as well as satisfactory antibacterial activity and kinetics. Our study offers a rational platform for synthesizing low-toxicity antibacterial polymers and provides fundamental insights into their structure-biological activity relationships.