A phage lysin fused to a cell-penetrating peptide kills intracellular methicillin-resistant Staphylococcus aureus in keratinocytes and has potential as a treatment for skin infections in mice

Abstract

Staphylococcus aureus is the main pathogen that causes skin and skin structure infections and is able to survive and persist in keratinocytes of the epidermis. Since the evolution of multidrug-resistant bacteria, the use of phages and their lysins has presented a promising alternative approach to treatment. In this study, a cell wall hydrolase (also called lysin) derived from Staphylococcus phage JD007 (JDlys) was identified. JDlys showed strong lytic activity against methicillin-resistant Staphylococcus aureus (MRSA) strains from different sources and of different multilocus sequence typing (MLST) types. Furthermore, a fusion protein consisting of a cellpenetrating peptide derived from the trans-activating transcription (Tat) factor fused to JDlys (CPPTat-JDlys) was used to kill MRSA bacteria causing intracellular infections. CPPTat-JDlys, in which the fusion of CPPTat to JDlys had almost no effect on the bacteriolytic activity of JDlys, was able to effectively eliminate intracellular MRSA bacteria and alleviate the inflammatory response and cell damage caused by MRSA. Specifically, CPPTat-JDlys was able to combat MRSA-induced murine skin infections and, consequently, expedite the healing of cutaneous abscesses. These data suggest that the novel antimicrobial CPP-JDlys may be a worthwhile candidate as a treatment for skin and skin structure infections caused by MRSA.