Low-Molecular-Weight Polylysines with Excellent Antibacterial Properties and Low Hemolysis

The steady development of bacterial resistance has become a global public health issue, and new antibacterial agents that are active against drug-resistant bacteria and less susceptible to bacterial resistance are urgently needed. Here, a series of low-molecular-weight cationic polylysines (C-PLL) with different hydrophobic end groups (C) and degrees of polymerization (PLL) was synthesized and used in antibacterial applications. All the obtained C-PLL have antibacterial activity. Among them, C₆-PLL₁₃ displays the best antibacterial effect for Gram-positive bacteria, that is, Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA), and highest selectivity against Gram-positive bacteria. A mechanistic study revealed that the C₆-PLL₁₃ destroys the integrity of the bacterial cell membrane and causes effective bacterial death. Owing to this membrane-disrupting property, C₆-PLL₁₃ showed rapid bacterial killing kinetics and was not likely to develop resistance after repeat treatment (up to 13 generations). Moreover, C₆-PLL₁₃ demonstrated a significant therapeutic effect on an MRSA infection mouse model, which further proved that this synthetic polymer could be used as an effective weapon against bacterial infections.