Researchers found that a naturally occurring skin peptide called lugdunin not only kills Staph aureus directly but also boosts the skin’s own defenses by making cells produce more of the antimicrobial peptide LL‑37 and other immune signals. When used together with other skin‑derived peptides, lugdunin cuts down bacterial colonisation even more, and it does this through a known immune pathway (TLR/MyD88). This suggests lugdunin could become a new topical tool for preventing or treating stubborn skin infections.

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.