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

Objectives: 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 (1–3). Methods: The antimicrobial and antibiofilm activities of asterripeptides A–C were tested using the Staphylococcus aureus ATCC 21027 strain. Human HaCaT keratinocytes infected with S. aureus 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 S. aureus-infected wounds were used according to ethical committee resolution. Results: Asterripeptides A–C (10 µM) inhibited S. aureus growth and biofilm formation. Asterripeptides A–C increased the viability, proliferation, and migration of S. aureus-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 S. aureus-infected incised wounds. Asterripeptide C significantly enhanced wound healing, normalized cytokine levels and profiles of peripheral blood samples, and decreased S. aureus contamination of wounds and blood in mice with infected incised wounds. Conclusions: 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.