Hydrocarbon-stapled lipopeptides exhibit selective antimicrobial activity

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Microbiology

Background:

• Antimicrobial peptides (AMPs) are natural compounds with therapeutic potential.
• Chemical modifications, including hydrocarbon stapling, can enhance AMP properties.
• Designing novel AMPs requires understanding structure-activity relationships.

Purpose of the Study:

• To design, synthesize, and evaluate hydrocarbon-stapled lipopeptides (HSLPs) for antimicrobial activity.
• To investigate the impact of peptide length, amphipathic character, and stapling on biological activity.
• To assess the membrane-disruptive and hemolytic properties of HSLPs.

Main Methods:

• Synthesis of N-terminally acylated, C-terminally amidated, and hydrocarbon-stapled lipopeptides.
• Antimicrobial assays against Gram-negative (E. coli), Gram-positive bacteria (S. aureus, B. megaterium, E. faecalis), and fungi (C. albicans).
• Liposome leakage assays to measure membrane disruption and hemolysis assays.

Main Results:

• HSLPs demonstrated broad-spectrum antimicrobial activity.
• Substitution with (S)-2-(4'-pentenyl)-alanine significantly increased antimicrobial activity, hemolysis, and membrane disruption.
• Stapled peptides showed slightly enhanced antimicrobial potency.
• Increased hydrophobicity correlated with greater hemolysis and liposome leakage but lower antimicrobial activity.

Conclusions:

• HSLPs are effective membrane-disruptive antimicrobial agents.
• Chemical modifications, such as hydrocarbon stapling and specific amino acid substitutions, can optimize antimicrobial efficacy.
• HSLPs exhibit potent antimicrobial activity with relatively low hemolytic potential at effective concentrations.