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

What was studied?

This study investigated the immunomodulatory and antimicrobial properties of lugdunin, a thiazolidine-containing cyclic peptide antibiotic produced by Staphylococcus lugdunensis, in the context of Staphylococcus aureus skin colonization. The authors assessed lugdunin’s capacity to enhance host innate immune responses and examined its synergy with both microbiota-derived and host-derived factors. Specifically, they explored lugdunin’s ability to induce antimicrobial peptides (AMPs) and cytokines in primary human keratinocytes (PHKs) and mouse skin, its dependence on the TLR/MyD88 signaling pathway, and its synergistic bactericidal activity with host AMPs.

Who was studied?

The study used multiple experimental models, including in vitro stimulation of human primary keratinocytes, nasal and tracheal epithelial cells, and peripheral blood mononuclear cells (PBMCs). Murine models (C57BL/6 wild-type, MyD88 knockout, and 5xTLR knockout mice) were employed for in vivo analysis of cytokine expression and immune cell recruitment in response to epicutaneous lugdunin application.

What were the most important findings?

Lugdunin acts through a dual mechanism—direct antimicrobial activity and immunomodulation—to inhibit S. aureus colonization. Pretreatment of human keratinocytes and murine skin with lugdunin significantly reduced S. aureus adherence and colonization, particularly when combined with S. epidermidis-derived conditioned media. Lugdunin potently induced LL-37 and CXCL8 (MIP-2 in mice) expression, facilitating neutrophil and monocyte recruitment to the application site via a Toll-like receptor (TLR)/MyD88-dependent mechanism. This was supported by impaired cytokine expression and immune cell infiltration in TLR- and MyD88-deficient mice, indicating a reliance on these innate pathways.

Notably, lugdunin exhibited a strong synergistic antimicrobial effect against MRSA (USA300) when combined with human AMPs LL-37 and dermcidin-derived peptides (DCD-1 and DCD-1L). Combination index analysis (Fig. 5 b, page 9) confirmed synergistic killing, whereas sequential peptide application failed to replicate this effect (Fig. 6, page 10), underscoring the importance of simultaneous exposure. These synergistic effects were specific to S. aureus, as they did not extend to commensal or Gram-negative species.

Additionally, lugdunin outperformed other bacteriocins like nisin and gallidermin in inducing CXCL8 expression and immune cell recruitment (page 8). Notably, the immunostimulatory activity required the intact thiazolidine ring structure, as N-acetyl-lugdunin lacked this function.

What are the greatest implications of this study?

The findings position lugdunin as a multi-functional, microbiota-derived molecule that enhances skin defense against S. aureus via synergistic antimicrobial and innate immune mechanisms. It establishes a new paradigm in which commensal-derived cyclic peptides can simultaneously suppress pathogens and amplify host defense pathways. This raises the possibility of using lugdunin, or lugdunin-producing commensals, as a topical therapeutic to reduce S. aureus burden, particularly in atopic dermatitis and MRSA-prone individuals. The synergistic interactions with host AMPs suggest a promising avenue for combination therapies that enhance cutaneous innate immunity without relying solely on conventional antibiotics.

Further, given this study’s findings, Lugdunin’s relevance extends far beyond acute Staphylococcus aureus skin infections. It holds substantial promise for broader therapeutic application in chronic conditions where S. aureus has been identified as a Major Microbial Association (MMA) in microbiome signatures.