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Antimicrobial peptides are known as immunomodulators and antibiotic enhancers. We report that administration of an antimicrobial peptide, IB-367, was efficacious in increasing the antimicrobial activity of daptomycin and teicoplanin in a mouse model of wound infection caused by meticillin-resistantStaphylococcus aureus(MRSA). Mice were assigned to seven groups: an IB-367 pre-treated group with no antibiotics given after challenge, two IB-367 pre-treated groups plus daptomycin or teicoplanin given after challenge, two groups treated with daptomycin or teicoplanin only after challenge, and two control groups without infection or that did not receive any treatment. The main outcome measures were quantitative bacterial culture and analysis of natural killer (NK) cytotoxicity and leukocyte phenotype. The wound, established through the panniculus carnosus muscle of mice, was infected by MRSA. Bacterial cultures of mice receiving antibiotics alone showed a −2 log decrease, whilst those for IB-367 plus daptomycin or teicoplanin showed a −4 log decrease. IB-367 plus daptomycin showed the highest efficacy. The higher antimicrobial effect exerted by IB-367 was associated with increased levels of NK cytotoxicity but not of NK cell number. IB-367 increased the number of both CD11b and Gr-1 cells 3 days after MRSA challenge, whereas both of these leukocyte populations were reduced at 10 days after challenge. Our data suggest that a combination of IB-367 with antibiotic exerts a therapeutic effect and may be useful for the management of staphylococcal wounds.