**Background:** Staphylococcus aureus is a versatile pathogen that colonizes 20–30% of the human population permanently in the nose, with another 30% carrying it intermittently. Nasal colonization is a risk factor for skin and soft tissue infections. Healthy skin presents a hostile environment with desiccation, low pH, constant shedding, and antimicrobial peptides. However, S. aureus can overcome these defenses and adapt to pathological conditions such as atopic dermatitis (AD) and diabetic foot ulcers (DFU), leading to persistent and recurrent infections. This narrative review synthesizes current knowledge on the metabolic, genotypic, and regulatory mechanisms underlying S. aureus adaptation to the skin in health and disease.
**Methods:** The authors conducted a comprehensive review of the literature, focusing on studies that examined S. aureus metabolic adaptation, genotypic diversity (via MLST, spa typing, WGS), and regulation of virulence factors (Agr, Sae, and other regulators) in the context of healthy skin, AD, and DFU. They included data from clinical cohorts, in vitro experiments, and animal models.
**Key Results:**
- **Metabolic adaptation:** In healthy skin, S. aureus neutralizes acidic pH by upregulating urease (converting urea to ammonia) and arginine deiminase (Arc, from ACME in USA300). In AD, isolates show increased expression of fumarase C (fumC) to promote glycolysis, which is essential for proliferation. In DFU, hypoxia drives upregulation of glycolysis and fermentation genes, and glucose-6-phosphate induces cytotoxin expression via the hexose phosphate transport system.
- **Genotypic diversity:** Among healthy nasal carriers, CC30 is a major clone (e.g., 47% of 829 isolates in the Netherlands). In AD patients, CC1 is prevalent, especially in those with filaggrin mutations (e.g., 50% of isolates in a Danish study). CC45 and CC5 are also common. In DFU, CC1, CC5, CC30, CC45, and CC398 are frequently found; CC398 is significantly associated with diabetic foot osteomyelitis (DFOM) in France, increasing from 4% in 2010 to 26% in 2017. MRSA prevalence in DFU varies from 10–15% in some regions to 40–85% in others.
- **Regulation of virulence:** The Agr quorum-sensing system is critical for AD pathogenesis. A functional agr is associated with increased risk of AD in infants, and RNAIII expression is upregulated in lesional skin of AD patients. In contrast, agr mutants are selected in chronic AD, favoring biofilm formation and intracellular persistence. In DFU, high glucose and AGEs downregulate agr, promoting biofilm and small colony variants (SCV). SCV are prevalent in DFOM (10% of MRSA isolates) and contribute to antibiotic tolerance and recurrence.
**Clinical Implications:** The review highlights that S. aureus adaptation to the skin is driven by niche-specific metabolic and regulatory changes. In AD, targeting the Agr system or promoting cross-inhibition by coagulase-negative staphylococci may reduce flares. In DFU, inhibiting biofilm formation (e.g., by blocking AGEs) and addressing SCV persistence could improve wound healing. The association of specific clones (e.g., CC398) with severe outcomes underscores the need for molecular surveillance. The high prevalence of MSSA in persistent infections (e.g., ST45, ST22 in DFU) indicates that antibiotic resistance is not the sole driver of chronicity. Future research should focus on longitudinal studies to distinguish reinfection from persistence and on the impact of host factors (e.g., Th2 milieu in AD, hypoxia in DFU) on bacterial adaptation.