Structure-based discovery of a small-molecule inhibitor of methicillin-resistant staphylococcus aureus virulence

The rapid emergence and dissemination of methicillin-resistant Staphylococcus aureus (MRSA) strains poses a major threat to public health. MRSA possesses an arsenal of secreted hostdamaging virulence factors that mediate pathogenicity and blunt immune defenses. Panton-Valentine leukocidin (PVL) and-toxin are exotoxins that create lytic pores in the host cell membrane. They are recognized as being important for the development of invasiveMRSAinfections and are thus potential targets for antivirulence therapies. Here, we report the highresolution X-ray crystal structures of both PVL and-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with n-tetradecylphosphocholine (C14PC). The structures revealed two evolutionarily conserved phosphatidylcholine-binding mechanisms and their roles in modulating host cell attachment, oligomer assembly, and membrane perforation. Moreover, we demonstrate that the solubleC14PCcompound protects primaryhumanimmunecells in vitro against cytolysis byPVL and-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.