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Design, synthesis and biological evaluation of Meucin-18 derived peptides as efficient broad-spectrum antibacterial
Xiaohong Chang1, Yangchun Ma1, Xianghui Zhang1
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, China.
Abstract:
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.
Insights
Researchers modified Meucin-18 to create CH-1, a peptide with enhanced antibacterial activity and reduced hemolytic toxicity. This new peptide shows promise for treating bacterial infections with improved safety and efficacy in vivo.
Area of Science:
- Biochemistry
- Microbiology
- Pharmacology
Background:
- Meucin-18 exhibits potent antibacterial activity but suffers from significant hemolytic toxicity, limiting its therapeutic potential.
- Structural modification of antimicrobial peptides is a viable strategy to improve their efficacy and safety profiles.
- Bacterial biofilms present a major challenge in treating persistent infections due to their inherent resistance.
Purpose of the Study:
- To design and synthesize novel peptide analogs of Meucin-18 with improved antibacterial potency and reduced hemolytic toxicity.
- To evaluate the antibacterial and antibiofilm activities of the derived peptides against relevant bacterial strains.
- To assess the in vivo safety and therapeutic efficacy of the most promising peptide candidate.
Main Methods:
- Peptide synthesis and structural modification of Meucin-18.
- Determination of minimum inhibitory concentration (MIC) and hemolytic activity.
- Assessment of biofilm inhibition assays.
- In vivo safety studies in Galleria mellonella and therapeutic efficacy studies in mice.
Main Results:
- Derived peptides, particularly CH-1, demonstrated significantly enhanced antibacterial activity and biofilm inhibition compared to Meucin-18.
- CH-1 exhibited markedly reduced hemolytic toxicity while maintaining potent membrane-lysing antibacterial action.
- In vivo studies showed good safety of CH-1 in Galleria mellonella and comparable therapeutic effects to vancomycin in mice.
- Structural analysis suggests an additional positive charge in CH-1 enhances electrostatic interaction with bacterial membranes.
Conclusions:
- The structural modification of Meucin-18 to CH-1 successfully yielded a peptide with superior antibacterial and antibiofilm properties and lower toxicity.
- CH-1 represents a promising candidate for further development as a therapeutic agent against bacterial infections.
- The enhanced positive charge is likely responsible for the improved efficacy and membrane interaction of CH-1.
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