Staphylococcus aureus virulence attenuation and immune clearance mediated by a phage lysin‐derived protein

New anti‐infective approaches are much needed to control multi‐drug‐resistant (MDR) pathogens, such as methicillin‐resistant Staphylococcus aureus (MRSA). Here, we found for the first time that a recombinant protein derived from the cell wall binding domain (CBD) of the bacteriophage lysin PlyV12, designated as V12CBD, could attenuate S. aureus virulence and enhance host immune defenses via multiple manners. After binding with V12CBD, S. aureus became less invasive to epithelial cells and more susceptible to macrophage killing. The expressions of multiple important virulence genes of S. aureus were reduced 2.4‐ to 23.4‐fold as response to V12CBD. More significantly, V12CBD could activate macrophages through NF‐κB pathway and enhance phagocytosis against S. aureus . As a result, good protections of the mice from MRSA infections were achieved in therapeutic and prophylactic models. These unique functions of V12CBD would render it a novel alternative molecule to control MDR S. aureus infections. Synopsis The recombinant phage lysin‐derived protein, V12CBD, attenuates Staphylococcus aureus virulence and enhances host innate immunity via different mechanisms, thus serving as a potential therapeutic and prophylactic candidate for anti‐virulence therapy. V12CBD reduces adhesion and invasion of S. aureus to epithelial cells, and sensitizes S. aureus to macrophage killing. V12CBD downregulates transcriptions of multiple virulence factors of S. aureus . V12CBD activates macrophage through NF‐κB pathway. Graphical Abstract The recombinant phage lysin‐derived protein, V12CBD, blocks Staphylococcus aureus virulence and enhances host innate immunity by activating macrophages via the NF‐KB pathway, providing a potential therapeutic candidate for anti‐virulence therapy.