Newly Identified Antimicrobial Peptide Scymicrosin_7–26 from <i>Scylla paramamosain</i> Showing Potent Antimicrobial Activity Against Methicillin-Resistant <i>Staphylococcus aureus</i> <i>In Vitro</i> and <i>In Vivo</i>

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a predominant pathogen causing skin and soft tissue infections, which significantly hinders the wound healing process and contributes to high mortality rates. The rise of multidrug-resistant bacteria, coupled with the limited availability of new antibiotics, underscores the pressing need for the development of innovative antimicrobial substances. Antimicrobial peptides (AMPs), with their multitargeted and rapid antimicrobial activity, are promising candidates to address this crisis. In this study, we identified a novel AMP, Scymicrosin_7-26, derived from <i>Scylla paramamosain</i>, which demonstrated potent antimicrobial activity against a variety of MDR strains, particularly MRSA. Confocal microscopy and transmission electron microscopy observations showed that Scymicrosin_7-26 bound to MRSA, and had a disruptive effect on cell walls and cell membranes, rapidly penetrating and killing MRSA. Notably, Scymicrosin_7-26 exhibited good stability under various ionic conditions, thermal stresses and certain serum concentration, had no obvious toxic effects on HaCaT cells, and its ability to penetrate HaCaT cells indicated its potential for intracellular targeted therapy. <i>In vitro</i>, Scymicrosin_7-26 significantly reduced the number of MRSA in HaCaT cells and inhibited intracellular MRSA proliferation. After verifying the low toxicity of Scymicrosin_7-26 <i>in vivo</i> in the Marine model organism─marine medaka (<i>Oryzias melastigma</i>), a wound model of MRSA-infected mice was made, and topical administration of Scymicrosin_7-26 in hypromellose gels could significantly reduce bacterial burden and promote wound closure. Histological analysis confirmed that Scymicrosin_7-26 alleviated tissue damage and was comparable to the effect of vancomycin treatment. Collectively, Scymicrosin_7-26 is promising for the treatment of MRSA wound infections and could be a valuable addition to the arsenal against antibiotic-resistant bacteria.