Improved Antibacterial Activity of the Marine Peptide N6 against Intracellular Salmonella Typhimurium by Conjugating with the Cell-Penetrating Peptide Tat11 via a Cleavable Linker

The poor penetration ability of antimicrobial agents limits their use in the treatment of intracellular bacteria. In this study, the conjugate CNC (6) was generated by connecting the cell-penetrating peptide Tat11 (1) and marine peptide N6 (2) via a cathepsin-cleavable linker, and the C-terminal aminated N6 (7) and CNC (8) were first designed and synthesized to eliminate intracellular Salmonellae Typhimurium. The cellular uptake of 6 and stability of 7 were higher than those of 2, and conjugates 6, 8, and 7 had almost no hemolysis and cytotoxicity. The antibacterial activities of 6, 8, and 7 against S. Typhimurium in RAW264.7 cells were increased by 67.2–76.2%, 98.6–98.9%, and 96.3–97.6%, respectively. After treatment with 1–2 μmol/kg of 6, 8, or 7, the survival of the S. Typhimurium–infected mice was 66.7–100%, higher than that of 2 (33.4–66.7%). This result suggested that 6, 8, and 7 may be excellent candidates for novel antimicrobial agents to treat intracellular pathogens.