期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 18, 页码 5944-5959出版社
ELSEVIER
DOI: 10.1074/jbc.RA120.012697
关键词
methicillin-resistant Staphylococcus aureus (MRSA); toxin; virulence factor; structural biology; drug discovery; antivirulence therapy; MRSA; pore-forming toxin; structure-based drug design; virulence factor; phosphatidylcholine; Panton-Valentine leukocidin (PVL); alpha-toxin; leukocidin ED (LukED)
资金
- National Institutes of Health [AI094599]
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 host-damaging 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 invasive MRSA infections and are thus potential targets for antivirulence therapies. Here, we report the high-resolution 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 soluble C14PC compound protects primary human immune cells in vitro against cytolysis by PVL and ?-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.
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