Engineered N-terminal modified α/β-hybrid peptides with enhanced selectivity and stability: Multi-target...

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Microbiology

Background:

• Clinical development of antibacterial peptides faces challenges like cytotoxicity, poor stability, and high costs.
• Traditional peptide modifications often fall short of addressing these limitations effectively.

Purpose of the Study:

• To design and synthesize novel short cationic α/β-hybrid peptides with enhanced stability, selectivity, and antibacterial efficacy.
• To investigate the multi-targeted mechanisms of action for these modified peptides.

Main Methods:

• Synthesis of α/β-hybrid peptides incorporating urea bonds and THPA moieties.
• Antimicrobial activity testing against Methicillin-resistant Staphylococcus aureus (MRSA).
• Mechanistic studies including membrane lysis, DNA interaction, and reactive oxygen species induction.

Main Results:

• Synthesized peptides (TH-01, TH-02, TH-03) demonstrated significant antimicrobial activity against MRSA (MIC 1.5-12.5 μM).
• Enhanced selectivity and structural stability were observed compared to traditional peptides.
• Peptides exhibit bactericidal effects through membrane lysis, genomic DNA interaction, and ROS generation.

Conclusions:

• The developed α/β-hybrid peptides represent a promising strategy for creating stable, selective, and effective antimicrobial agents.
• These novel peptides offer a potential new avenue for combating antimicrobial resistance through multi-targeted mechanisms.