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 Tat 11 ( 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.