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

Abstract

Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits S taphylococcus 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.

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

“…Other factors derived from the skin commensal S. epidermidis may serve to amplify this response, increasing efficacy. 179 SAR studies indicate that the cyclic structure of the peptide, the N-unsubstituted thiazolidine "clasp", two amino acids tryptophan and leucine, and an alternating D-and L-amino acid backbone are integral to the activity. 175 The nonpolar tryptophan and leucine residues interact with the hydrophobic regions of the bacterial cell membranes similar to the activity of poly-(Trp-Leu)-octapeptides.…”

Novel Research Models for Staphylococcus aureus Small Colony Variants (SCV) Development: Co-pathogenesis and Growth Rate

“…The mechanism of action of lugdunin against S. aureus has not been determined, and so whether this bactericidal effect selects for SCV is unclear. However, it has been shown to act synergistically with the innate immune response, where lugdunin increases recruitment of monocytes and neutrophils to keratinocytes (Bitschar et al, 2019).…”

Staphylococcus aureus Host Tropism and Its Implications for Murine Infection Models

“…Iwase et al showed that the serine protease Esp, which is produced by the commensal Staphylococcus epidermidis, inhibits S. aureus biofilm formation and nasal colonization [ 134 ]. Other bacteria interfering with S. aureus colonization are, for instance, Staphylococcus lugdunensis via a peptide antibiotic called lugdunin [ 135 ], as well as certain Bacillus species that produce fengycin lipopeptides, which interfere with S. aureus quorum sensing and thereby disrupt colonization [ 136 ].…”