Quaternary Ammonium Salt Derivatives of Hyperbranched\nPolylysine with Enhanced Antibacterial Activity against Multidrug-Resistant\nGram-Negative Bacteria

Multidrug-resistant (MDR) Gram-negative\nbacteria infections have\ngradually become a more serious health problem recently, and antibacterial\ndrugs are urgently needed to tackle MDR Gram-negative bacteria. Herein,\nwe synthesized a series of quaternary ammonium salt derivatives of\nhyperbranched polylysine (HPL-<i>Cm</i>-<i>n</i>) with different alkyl chain lengths (<i>m</i> = 4, 8,\n12, 16) and grafting ratios (<i>n</i> = 5.8–21.0)\nof alkyl quaternary ammonium salts (<i>Cm</i>). HPL-<i>Cm</i>-<i>n</i>s exhibited excellent antibacterial\nactivities against drug-sensitive <i>E. coli</i> and <i>P. aeruginosa</i>, and specifically, HPL-C12-<i>n</i>s were also highly active against MDR <i>E. coli</i> and <i>P. aeruginosa</i>. The cytotoxicity and hemolytic activity of\nHPL-<i>Cm</i>-<i>n</i>s increased with the increase\nin the alkyl chain length and the grafting ratio of <i>Cm</i>. The killing study proved that HPL-C12-9.5 had fast killing kinetics\nand was bactericidal toward both drug-sensitive and MDR <i>E.\ncoli</i>. The mechanistic studies showed that, similar to hyperbranched\npolylysine (HPL), HPL-C12-9.5 killed bacteria by disrupting the cell\nmembranes and causing leakage of the cytoplasmic contents. HPL-C12-<i>n</i>s might have potential as an antibacterial agent to combat\nMDR Gram-negative bacteria.