Quaternary Ammonium Salt Derivatives of Hyperbranched Polylysine with Enhanced Antibacterial Activity against Multidrug-Resistant Gram-Negative Bacteria

Multidrug-resistant (MDR) Gram-negative bacteria infections have gradually become a more serious health problem recently, and antibacterial drugs are urgently needed to tackle MDR Gram-negative bacteria. Herein, we synthesized a series of quaternary ammonium salt derivatives of hyperbranched polylysine (HPL-Cm-n) with different alkyl chain lengths (m = 4, 8, 12, 16) and grafting ratios (n = 5.8–21.0) of alkyl quaternary ammonium salts (Cm). HPL-Cm-ns exhibited excellent antibacterial activities against drug-sensitive E. coli and P. aeruginosa, and specifically, HPL-C12-ns were also highly active against MDR E. coli and P. aeruginosa. The cytotoxicity and hemolytic activity of HPL-Cm-ns increased with the increase in the alkyl chain length and the grafting ratio of Cm. The killing study proved that HPL-C12-9.5 had fast killing kinetics and was bactericidal toward both drug-sensitive and MDR E. coli. The mechanistic studies showed that, similar to hyperbranched polylysine (HPL), HPL-C12-9.5 killed bacteria by disrupting the cell membranes and causing leakage of the cytoplasmic contents. HPL-C12-ns might have potential as an antibacterial agent to combat MDR Gram-negative bacteria.