Staphylococcus aureus Accessory Gene Regulator Quorum-sensing System Inhibits Keratinocyte Lipid Enzymes and Delays Wound Repair

In a 2025 study by Bagood et al, the activation of the Staphylococcus aureus (S. aureus) gene regulator (agr) quorum-sensing system was shown to impair keratinocyte lipid metabolism and significantly delay wound healing, suggesting that targeting quorum sensing could be a promising nonantibiotic strategy to improve outcomes in chronic wound care.¹

Background and Study Results

Cutaneous wounds such as diabetic foot ulcers, secondary wounds associated with atopic dermatitis, and chronic venous leg ulcers are often complicated by S. aureus infection, especially methicillin-resistant strains (MRSA).² These strains are strongly associated with delayed healing and increased morbidity. Biofilm formation, antimicrobial resistance, and bacterial density-dependent virulence all contribute to impaired tissue repair.3 However, the precise molecular mechanisms by which S. aureus disrupts reepithelialization remain unclear.

Bagood et al investigated whether quorum sensing via the S. aureus agr system alters host wound-healing responses. Using murine wound models, human keratinocyte cultures, and transcriptomic analysis, the authors compared pathogenic S. aureus with the commensal species Staphylococcus hominis. Wounds inoculated with S. aureus demonstrated significantly delayed closure and persistent bacterial burden, whereas S. hominis did not impair healing.

Spatial and bulk RNA sequencing revealed that S. aureusinfection suppressed expression of genes involved in fatty-acid and lipid metabolism in keratinocytes. These pathways are essential for restoring the epidermal barrier during reepithelialization. These transcriptional changes were also seen in nonhealing diabetic foot ulcers. In-vitro studies showed exposure to S. aureus products inhibited keratinocyte migration and proliferation. This further demonstrated a direct effect on wound repair mechanisms.

Deletion of the agr quorum-sensing system (SaΔagr) eliminated these effects. Wounds healed normally, lipid-metabolism gene expression was restored, and keratinocyte function improved. Additional experiments showed that multiple agr-controlled virulence factors, such as phenol-soluble modulins and toxins, contributed collectively to impaired healing. This suggests that coordinated quorum-sensing activity, rather than a single toxin, drives the pathology.

Comments/Clinical Implications

This study provides compelling insight into how S. aureus can delay wound healing by shifting keratinocytes away from regenerative lipid synthesis toward inflammatory and host-defense pathways. These findings highlight keratinocyte lipid metabolism as a previously underrecognized target of bacterial virulence and underscore the importance of microbial signaling in chronic wound healing.

These results suggest that therapies aimed at inhibiting agr quorum sensing could be a novel, nonantibiotic strategy to improve healing outcomes while avoiding selective pressure for antimicrobial resistance. This approach may be particularly valuable given the high prevalence of antibiotic-resistant S. aureus and the need for alternative treatments in chronic wound care.

Some of the limitations include reliance on a highly virulent MRSA strain and experimental models that may not fully replicate the polymicrobial environment of real wounds. Future studies are needed to evaluate quorum-sensing inhibition in diverse clinical isolates and to determine whether targeted modulation of bacterial signaling can translate into effective therapies for chronic wound care.