Positive Charge-Concentrated Dimeric Lipopeptides with Enhanced Protease Resistance: A Potential Solution for...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) are potential antibiotic alternatives but are limited by protease susceptibility.
• Existing AMPs face challenges in broader clinical application due to degradation by enzymes.

Purpose of the Study:

• To engineer lipopeptides with enhanced protease resistance for improved antimicrobial applications.
• To investigate the effects of charge and hydrophobicity distribution on lipopeptide membrane interaction and efficacy.

Main Methods:

• Development of engineered lipopeptides utilizing antienzymolysis modifications and cysteine (Cys)-dimerization.
• Strategic placement of disulfide bonds to concentrate hydrophobicity and positive charges within the peptide sequence.
• In vitro and in vivo evaluation of protease resistance, stability, activity, and toxicity of engineered lipopeptides.

Main Results:

• Engineered lipopeptides, particularly the positive charge-concentrated dimeric lipopeptide (C-C10)C-C, exhibited significant protease resistance.
• (C-C10)C-C demonstrated excellent in vitro stability and activity, effectively clearing systemic bacterial infections in mice.
• No in vivo toxicity was observed for the engineered lipopeptide (C-C10)C-C.
• Bactericidal mechanisms involved synergistic membrane cleavage and energy metabolism inhibition.

Conclusions:

• Cysteine-dimerization and strategic charge/hydrophobicity distribution enhance AMP protease resistance and efficacy.
• Engineered lipopeptides represent a viable strategy for developing novel antimicrobial agents against bacterial infections.
• This approach offers insights for designing improved peptide-based biomaterials with enhanced stability.