Public Health Research Institute, Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey 07103.
Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032.
J Biol Chem. 2020 May 1;295(18):5944-5959. doi: 10.1074/jbc.RA120.012697. Epub 2020 Mar 16.
The rapid emergence and dissemination of methicillin-resistant (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 α-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 α-toxin in their soluble, monomeric, and oligomeric membrane-inserted pore states in complex with -tetradecylphosphocholine (CPC). 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 CPC compound protects primary human immune cells against cytolysis by PVL and α-toxin and hence may serve as the basis for the development of an antivirulence agent for managing MRSA infections.
耐甲氧西林金黄色葡萄球菌（MRSA）菌株的迅速出现和传播对公共健康构成了重大威胁。MRSA 拥有一系列分泌的宿主损伤毒力因子，介导致病性并削弱免疫防御。杀白细胞素（PVL）和 α-毒素是外毒素，可在宿主细胞膜上形成溶孔。它们被认为是侵袭性 MRSA 感染发展的重要因素，因此是抗毒力治疗的潜在靶点。在这里，我们报告了 PVL 和 α-毒素在与十四烷基磷酸胆碱（CPC）结合时的可溶性、单体和寡聚插入膜孔状态的高分辨率 X 射线晶体结构。这些结构揭示了两种进化保守的磷脂酰胆碱结合机制及其在调节宿主细胞附着、寡聚体组装和膜穿孔中的作用。此外，我们证明可溶性 CPC 化合物可防止原代人免疫细胞被 PVL 和 α-毒素溶解，因此可能成为开发抗毒力剂以治疗 MRSA 感染的基础。
