The combined effects of tick defensin persulcatusin with conventional antibiotics and antimicrobial proteins/peptides against Staphylococcus aureus

Persulcatusin (IP) is a tick defensin isolated from <i>Ixodes persulcatus</i> and is composed of 38 aa (molecular weight of 4,200). IP exhibits potent antimicrobial activity against <i>Staphylococcus aureus</i>, including drug-resistant strains, such as methicillin- and vancomycin-resistant <i>S. aureus</i>. Despite its potential use as an anti-<i>S. aureus</i> drug, its application remains underdeveloped because of several limitations, such as manufacturing costs and <i>in vivo</i> safety. Here, the combined effect of IP and other conventional antibiotics and antimicrobial proteins/peptides against <i>S. aureus</i> bacterial infections was investigated. Combinations of several antimicrobial compounds, including <i>β</i>-lactams, peptide antibiotics and lytic enzymes, showed a synergistic effect against <i>S. aureus</i> with a fractional inhibitory concentration index (FICI) of ≤0.75. In contrast, IP had an additive or irrelevant effect with a FICI of 1.0-2.0 when combined with several antibiotics such as chloramphenicol, gentamycin, kanamycin, erythromycin or vancomycin. Interestingly, <i>S. aureus</i> cells pretreated with IP for a short time demonstrated reduced susceptibility to daptomycin. Furthermore, it was determined that the mode of bactericidal activity of IP was substantially different in growth and non-growth states, suggesting that the mechanism of action of IP was associated with the inhibition of bacterial biosynthesis. These findings indicated that the combined effect of IP and conventional antibiotics has the potential to be used as an effective antimicrobial drug against <i>S. aureus</i>. Furthermore, it also suggested that an unknown mechanism of action of IP was associated with the inhibition of bacterial cell biosynthesis.