Unveiling the Role of Alkyl Chain in Boosting Antibacterial Selectivity and Cell Biocompatibility

Cationic amphiphiles have been demonstrated to be superior targeted antibacterial agents whose antibacterial activity exhibits a close relationship with their alkyl chain substituents. However, a systematic and deep investigation of the structure-property relationship is still pending. Meanwhile, cationic amphiphiles have a risk of accumulating in living mammalian cells, which poses a great threat to biosafety and clinical applications. In this study, a series of cationic amphiphilic aggregation-induced emission luminogens (AIEgens) with different alkyl chains (TPD-4, TPD-6, and TPD-12) have been developed with selective and variable antibacterial activity against Gram-positive bacteria depending on the alkyl chain length. Among them, TPD-6 with the intermediate alkyl chain length exhibited superior Gram-positive antibacterial performance. In addition, these cationic amphiphilic AIEgens had negligible invasiveness to mammalian cells. Molecular dynamics simulations revealed that the binding and deforming capabilities of the cationic amphiphilic AIEgens to the phospholipid bilayer of bacteria are responsible for their antibacterial activity. In vivo experiments indicated that TPD-6 also exhibited significant antibacterial and wound-healing abilities against Gram-positive bacteria.