Antibiotic-conjugated antimicrobial peptides for enhanced bacterial inhibition

Herein, we report a pair of paenipeptin C'-based antimicrobial linear lipopeptides that significantly enhance bacterial inhibition through conjugation to antibiotics. When co-incubated with <i>Escherichia coli</i> or <i>Staphylococcus aureus</i>, these peptides induce bacterial death. The antimicrobial peptides target negatively charged bacterial membranes <i>via</i> electrostatic interactions, subsequently disrupting membrane integrity through aggregation and insertion, leading to membrane rupture and cytoplasmic leakage, as evidenced by bacterial morphology studies. Lipopeptides with longer alkyl chains penetrate deeper into the membrane structure, demonstrating stronger antibacterial effects. Additionally, the conjugated antibiotics may enhance bactericidal activity by inhibiting intracellular DNA gyrase. Therapeutic efficacy was further validated in a murine infected wound model. This work not only develops a class of broad-spectrum antimicrobial lipopeptides but also provides a novel strategy for developing antibiotic-conjugated antimicrobial peptides to enhance multiple antibacterial inhibition with minimal side effects.