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Severe skin and soft-tissue infections can lead to septic shock and organ failure. Antibiotic treatment is turning ineffective due to the rise of antimicrobial resistance. This calls for the need for novel antimicrobial therapies such as antimicrobial peptides. These peptides are small molecules that show antimicrobial activity and immune-related functions. The aim of this study was to determine the possible activity of the newly synthesized collagen-based REI-26 and cyclic CD4-PP in wound infections. REI-26 and CD4-PP antimicrobial activity were determined by measurement of MICvalues against S. aureus, MRSA, P. aeruginosa and Group A Streptococci. AMP treatment in vitro of infected keratinocytes and macrophages was also performed. The impact of treatment on immune-related and proliferation markers was assessed by quantitative PCR and confocal microscopy. Both studied synthetic AMPs showed antimicrobial activity at low concentrations whenMIC values were measured. Infected keratinocytes and macrophages with common skin bacterial pathogens showed a decrease in bacterial load only when treated with the cyclicCD4-PP. In contrast, REI-26 treatment showed either no reduction or an increase in bacterial load. Upregulation of immune chemokines and AMPs and downregulation of proliferation markers were observed when keratinocytes were treated with CD4-PP. The novel cyclic antimicrobial peptide, CD4-PP, presented promising results in treating skin bacterial infections, with optimal antimicrobial activity in MIC values and survival assays. Further research is required in order to adapt CD4-PP treatment to a clinical setting.