The Effects of Marine Fungal Asterripeptides A–C on In Vitro and In Vivo Staphylococcus aureus Skin Infection

<b>Objectives:</b> This study aimed to investigate the in vitro and in vivo antibacterial and cytoprotective activities of marine fungal tripeptide derivatives with cinnamic acid moiety asterripeptides A-C (<b>1</b>-<b>3</b>). <b>Methods:</b> The antimicrobial and antibiofilm activities of asterripeptides A-C were tested using the <i>Staphylococcus aureus</i> ATCC 21027 strain. Human HaCaT keratinocytes infected with <i>S. aureus</i> were used for the in vitro investigation of the various aspects of the influence of asterripeptides A-C by lumino- and fluorospectrometry, ELISA, flow cytometry, Western blotting, and microscopy techniques. In the in vivo experiments, mice with burns and scalped <i>S. aureus</i>-infected wounds were used according to ethical committee resolution. <b>Results:</b> Asterripeptides A-C (10 µM) inhibited <i>S. aureus</i> growth and biofilm formation. Asterripeptides A-C increased the viability, proliferation, and migration of <i>S. aureus</i>-infected HaCaT cells and reduced the release of reactive oxygen species (ROS), NO, TNF-α, and IL-18. Asterripeptides A-C protected HaCaT cells against TNF-α-induced inflammation, decreased the transcriptional level of NF-κB in JB6 Cl41 cells, and increased the protein levels of Nrf2 and glutathione synthetase in HaCaT cells. More active asterripeptide C was tested in in vivo burn wounds and <i>S. aureus</i>-infected incised wounds. Asterripeptide C significantly enhanced wound healing, normalized cytokine levels and profiles of peripheral blood samples, and decreased <i>S. aureus</i> contamination of wounds and blood in mice with infected incised wounds. <b>Conclusions:</b> Taken together, these results confirm the dual antibacterial and Nrf2-dependent anti-inflammatory activities of asterripeptides A-C in in vitro and in vivo assays.