Phage‐displayed heptapeptide sequence conjugation significantly improves the specific targeting ability of antimicrobial peptides against Staphylococcus aureus

Broad‐spectrum antibacterial drugs often lack specificity, leading to indiscriminate bactericidal activity, which can disrupt the normal microbial balance of the host flora and cause unnecessary cytotoxicity during systemic administration. In this study, we constructed a specifically targeted antimicrobial peptide against Staphylococcus aureus by introducing a phage‐displayed peptide onto a broad‐spectrum antimicrobial peptide and explored its structure–function relationship through one‐factor modification. SFK2 obtained by screening based on the selectivity index and the targeting index showed specific killing ability against S. aureus. Moreover, SFK2 showed excellent biocompatibility in mice and piglet, and demonstrated significant therapeutic efficacy against S. aureus infection. In conclusion, our screening of phage‐derived heptapeptides effectively enhances the specific bactericidal ability of the antimicrobial peptides against S. aureus, providing a theoretical basis for developing targeted antimicrobial peptides. Impact statement In treating diseases caused by microbial infections, broad‐spectrum antimicrobial peptides often lead to dysbiosis of the host flora and are prone to unwanted toxicity. In this study, we used phage display technology to screen for heptapeptide sequences that can specifically bind Staphylococcus aureus and modify them to obtain antimicrobial peptides with specific recognition abilities. The targeted peptide, SFK2, exerted antimicrobial effects by disturbing the structure of the bacterial membrane and showed good therapeutic effects in vivo. This study provides a reference for designing and developing targeted antimicrobial peptides.