Dual-Action Topical Therapy Accelerates Healing of MRSA-Infected Burn Wounds by Targeting Infection and Inflammation

<b>Objective:</b> Burn injuries affect over 11 million people annually, and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infection significantly delays healing by sustaining inflammation and promoting scarring. This study evaluated <i>N</i>-benzyl benzenamine 4k-a novel dual-action compound with antibacterial and anti-inflammatory properties-in a murine model of MRSA-infected burn wounds. <b>Approach:</b> Skin safety of 4k was assessed through acute toxicity, sensitization, and irritation tests in BALB/c mice. A full-thickness burn model infected with MRSA2858 (1 × 10⁸ CFU/mL) was treated topically with 4k, vancomycin (VAN), or vaseline. Outcomes included wound closure, bacterial load, histology, collagen organization, macrophage polarization markers (CD86/inducible nitric oxide synthase [iNOS] for M1; CD206/vascular endothelial growth factor [VEGF] for M2), cytokine levels, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway proteins. <b>Results:</b> 4k demonstrated excellent dermal tolerability with no toxicity or irritation. Topical 4k reduced MRSA colonization and accelerated wound closure (residual wound area at day 15: 4k = 8.4 ± 2.2%, VAN = 17.8 ± 3.5%). Histology revealed organized collagen deposition and minimal scarring in the 4k group (scar score: 2.33 ± 0.58 vs. 13.33 ± 0.58 for vaseline). Mechanistically, 4k suppressed NF-κB activation, downregulated M1 markers (CD86, iNOS, tumor necrosis factor-alpha, and interleukin [IL]-6), and upregulated M2 markers (CD206, VEGF, transforming growth factor-beta 1, and IL-10), promoting a prohealing immune environment. <b>Innovation:</b> This study introduces a dual-action topical therapy that combines potent antibacterial activity with immunomodulation, offering a promising strategy to overcome antibiotic resistance and improve burn wound outcomes. <b>Conclusions:</b> <i>N</i>-benzyl benzenamine 4k effectively eradicates MRSA, accelerates wound healing, and minimizes scarring through NF-κB inhibition and macrophage polarization, supporting its potential as a next-generation burn care agent.