The atopic dermatitis-like lesion and the associated MRSA infection and barrier dysfunction can be alleviated by 2,4-dimethoxy-6-methylbenzene-1,3-diol from Antrodia camphorata

Background: Atopic dermatitis (AD) is an inflammatory skin disease with an associated barrier dysfunction and Staphylococcus aureus infection. The mainstay steroid and calcineurin inhibitor therapy shows some adverse effects. 2,4-Dimethoxy-6-methylbenzene-1,3-diol (DMD) is a benzenoid isolated from Antrodia camphorata. Objective: We investigated the inhibitory effect of DMD on methicillin-resistant S. aureus (MRSA), the chemokine production in stimulated keratinocytes, and the AD-like lesion found in ovalbumin (OVA)-sensitized mice. Methods: The antimicrobial effect and cutaneous barrier function were evaluated using an in vitro culture model and an in vivo mouse model of AD-like skin. Results: DMD exhibited a comparative minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against MRSA with nalidixic acid, a conventional antibiotic. The MIC and MBC for DMD was 78.1 and 156.3 μg/ml, respectively. DMD also showed the ability to eliminate the clinical bacteria isolates with resistance to methicillin and vancomycin. The DNA polymerase and gyrase inhibition evoked by DMD for bacterial lethality was proposed. In the activated keratinocytes, DMD stopped the upregulation of chemokines (CCL5 and CCL17) and increased the expression of differentiation proteins (filaggrin, involucrin, and integrin β-1). Topical application of DMD facilely penetrated into the skin, with AD-like skin displaying 2.5-fold greater permeation than healthy skin. The in vivo assessment using the mouse model with OVA sensitization and MRSA inoculation revealed a reduction of transepidermal water loss (TEWL) and bacterial burden by DMD by about 2- and 100-fold, respectively. Differentiation proteins were also restored after topical DMD delivery. Conclusion: Our data demonstrated an advanced concept of AD treatment by combined barrier repair and bacterial eradication with a sole agent for ameliorating the overall complications.