Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors

Nat Commun. 2019 Jun 21;10(1):2730. doi: 10.1038/s41467-019-10646-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Antimicrobial Cationic Peptides / immunology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate / drug effects*
  • Keratinocytes / drug effects
  • Keratinocytes / immunology
  • Keratinocytes / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microbiota / drug effects
  • Microbiota / immunology
  • Peptides / immunology
  • Peptides, Cyclic / pharmacology*
  • Peptides, Cyclic / therapeutic use
  • Primary Cell Culture
  • Skin / drug effects
  • Skin / immunology
  • Skin / microbiology
  • Staphylococcal Infections / drug therapy*
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects*
  • Thiazolidines / pharmacology*
  • Thiazolidines / therapeutic use

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Peptides
  • Peptides, Cyclic
  • Thiazolidines
  • dermcidin
  • lugdunin
  • ropocamptide