New antimicrobial peptide kills drug-resistant pathogens without detectable resistance

Area of Science:

• Marine biotechnology
• Antimicrobial peptide research
• Dermatology

Background:

• Clavaspirin peptide (CSP) from *Styela clava* exhibits low antimicrobial and high hemolytic activity.
• Modifications were needed to enhance antimicrobial efficacy and reduce cytotoxicity.

Purpose of the Study:

• To design and evaluate CSP analogs with reduced hydrophobicity for improved antimicrobial properties.
• To assess the efficacy and safety of CSP-4 as a topical antimicrobial agent against drug-resistant *Staphylococcus aureus* (DRSA).

Main Methods:

• Synthesis of 4 CSP analogs with substituted hydrophobic amino acids.
• In vitro antimicrobial and hemolytic activity assays at different pH levels.
• In vivo efficacy study on a mouse model of DRSA skin infection.
• Analysis of skin penetration, inflammation markers (TLR-2, NF-κB, TNF-α, IL-1β), and collagen/elastin integrity.

Main Results:

• CSP analogs demonstrated reduced aggregation and cytotoxicity at pH 7.4.
• Analogs exhibited potent antimicrobial activity against Gram-negative and Gram-positive bacteria at pH 5.5 and 7.4.
• CSP-4 did not induce resistance in *Staphylococcus aureus* after prolonged exposure.
• Topical CSP-4 significantly reduced DRSA skin infections in mice with minimal dermal damage.
• CSP-4 penetrated the dermis and reduced key inflammatory markers.

Conclusions:

• CSP-4 is a potent antimicrobial agent with low cytotoxicity and no induced resistance.
• CSP-4 effectively treats DRSA skin infections by modulating inflammatory pathways.
• CSP-4 shows promise as a novel topical antimicrobial for skin diseases caused by DRSA.