Design, synthesis and biological evaluation of Meucin-18 derived peptides as efficient broad-spectrum antibacterial agents.

The cell lysis effect of Meucin-18 enhances its antibacterial activity (MIC = 3 μM against S. aureus AB208193), but also leads to considerable toxicity, as nearly complete hemolysis is observed at 12.5 μM, thereby limiting its potential for further development and application. In this paper, we modified the structure of Meucin-18 in an attempt to obtain derived peptides with stronger antibacterial activity or less hemolytic toxicity. The results showed that the derived peptide CH-1, CH-1-1, CH-1-2, and CH-1-3 exhibited much more potent antibacterial activity and stronger biofilm inhibitory effect than Meucin-18. CH-1 significantly lysed bacterial cell membranes, leading to bacterial death, and exhibited lower hemolysis toxicity than Meucin-18. CH-1 exhibits good in vivo safety. At a dose of 500 mg/kg, it does not cause the death of galleria mellonella, and at 1000 mg/kg, the survival rate can still reach 66.6 %. Additionally, the in vivo therapeutic effects of CH-1 (15 mg/kg) in mice are comparable to those of VAN (15 mg/kg). CH-1 is a derived peptide obtained by replacing the fourth histidine of Meucin-18 with arginine, which has one more positive charge than Meucin-18. The additional positive charge further strengthened the electrostatic interaction of CH-1 with bacterial membrane. This may be the possible reason why CH-1 has excellent antibacterial effect. Overall, the design of the derived peptide CH-1 is successful and can be further evaluated for its druggability in future research.