Tertiary alkylamine-functionalized polyaspartamides with potent antibacterial activity

Tertiary alkylamines serve as privileged structural motifs ubiquitously distributed across natural products, pharmaceutical agents, and bioactive molecules. However, their application in the design of antibacterial polymers has not been extensively explored. Here, a series of cationic polyaspartamides (PASP-n) with different tertiary alkylamine pendants were synthesized and screened for combatting methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) induced infections. Among all the synthesized PASP-n, the polymer bearing <i>N</i>, <i>N</i>-dibutylamine groups (PASP-4) exhibited the best antibacterial activity and the highest selectivity (>640 and > 160 for <i>S. aureus</i> and <i>E. coli</i>, respectively). The mechanistic study revealed that, due to the relative longer alkyl chain, PASP-4 could effectively bind with bacteria-specific anionic phosphatidylglycerol (POPG), thereby destroying the integrity of the bacterial membrane and resulting in the leakage of cytoplasmic components (<i>e.g.</i>, ATP, DNA, and K⁺). Owing to this membrane disrupting ability, PASP-4 showed rapid bacterial killing kinetics without developing bacteria resistance after repeated treatments over 28 generations. Furthermore, PASP-4 demonstrated significant therapeutic potential in both local and systemic MRSA infections. Overall, this study proposes a viable strategy for the rational design of antibacterial polymers based on tertiary alkylamine structures.