| Summary: | <i>Staphylococcus aureus </i>is a microorganism capable of causing numerous diseases of the human skin. The incidence of <i>S. aureus </i>skin infections reflects the conflict between the host skin′s immune defenses and the <i>S. aureus’</i> virulence elements. Antimicrobial peptides (AMPs) are small protein molecules involved in numerous biological activities, playing a very important role in the innate immunity. They constitute the defense of the host′s skin, which prevents harmful microorganisms from entering the epithelial barrier, including <i>S. aureus.</i> However, <i>S. aureus</i> uses ambiguous mechanisms against host defenses by promoting colonization and skin infections. Our review aims to provide a reference collection on host–pathogen interactions in skin disorders, including <i>S. aureus</i> infections and its resistance to methicillin (MRSA). In addition to these, we discuss the involvement of defensins and other innate immunity mediators (i.e., toll receptors, interleukin-1, and interleukin-17), involved in the defense of the host against the skin disorders caused by <i>S. aureus</i>, and then focus on the evasion mechanisms developed by the pathogenic microorganism under analysis. This review provides the “state of the art” on molecular mechanisms underlying <i>S. aureus</i> skin infection and the pharmacological potential of AMPs as a new therapeutic strategy, in order to define alternative directions in the fight against cutaneous disease.
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