lugdunin and Disease-Models--Animal

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.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cathelicidins; Cells, Cultured; Disease Models, Animal; Female; Humans; Immunity, Innate; Keratinocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Peptides; Peptides, Cyclic; Primary Cell Culture; Skin; Staphylococcal Infections; Staphylococcus aureus; Thiazolidines

The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.

Topics: Animals; Anti-Bacterial Agents; Carrier State; Disease Models, Animal; Drug Resistance, Microbial; Female; Humans; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Microbiota; Nose; Peptides, Cyclic; Sigmodontinae; Staphylococcal Infections; Staphylococcus aureus; Staphylococcus lugdunensis; Symbiosis; Thiazolidines