Bacterial phospholipid selective quaternary phosphonium polymers with potent antibacterial activity

Cationic polymers hold strong promise for treating bacterial infections. Most reported cationic antibacterial polymers incorporate nitrogen-containing moieties, including primary, secondary, or quaternary amine group, whereas phosphonium-based antibacterial polymer was less reported and their structure-activity relationships have not been systematically elucidated. In this work, a series of polymers bearing different quaternary phosphonium side chains (CP-n) were synthesized. Among these polymers, the polymer with tripropylphosphine side group (brief named as CP-3) shown best antibacterial activity (MIC = 2 μg/mL against S. aureus) and highest selectivity index (SI = 100). Mechanistic study further demonstrated that, compared with the zwitterionic phosphocholine (DOPC) in mammalian membranes, CP-3 can selectively bind to the anionic bacterial-specific phospholipids phosphatidylglycerol (POPG) through electrostatic interactions, thereby effectively disrupt bacterial membrane integrity. Due to the unique bacterial phospholipids targeting ability and membrane damaging mechanism, CP-3 demonstrates rapid bactericidal kinetics with low tendency to induce bacterial resistance. Notably, CP-3 effectively inhibits S. aureus biofilm formation and disrupts mature S. aureus biofilms. Furthermore, CP-3 demonstrated strong therapeutic potential in MRSA-induced lung infection and peritonitis. Hence, this work provides a new strategy for the design of phosphonium-based antibacterial polymers.