LAUSR

Staphylococcus aureus is a major infectious agent responsible for a plethora of superficial skin infections and systemic diseases, including endocarditis and septic arthritis. Recent epidemiological data revealed the emergence of resistance to commonly used antibiotics, including increased numbers of both hospital- and community-acquired methicillin-resistant S. aureus (MRSA). Due to their potent antimicrobial functions, low potential to develop resistance, and immunogenicity, antimicrobial peptides (AMPs) are a promising alternative treatment for multidrug-resistant strains. Here, we examined the activity of a lysine-rich derivative of amphibian temporin-1CEb (DK5) conjugated to peptides that exert pro-proliferative and/or cytoprotective activity. Analysis of a library of synthetic peptides to identify those with antibacterial potential revealed that the most potent agent against multidrug-resistant S. aureus was a conjugate of a temporin analogue with the synthetic Leu-enkephalin analogue dalargin (DAL). DAL-PEG-DK5 exerted direct bactericidal effects via bacterial membrane disruption, leading to eradication of both planktonic and biofilm-associated staphylococci. Finally, we showed that accumulation of the peptide in the cytoplasm of human keratinocytes led to a marked clearance of intracellular MRSA, resulting in cytoprotection against invading bacteria. Collectively, the data showed that DAL-PEG-DK5 might be a potent antimicrobial agent for treatment of staphylococcal skin infections.