University of Colorado Anschutz Medical Campus, Department of Immunology and Microbiology, Aurora, Colorado, United States of America.
PLoS Pathog. 2022 Mar 22;18(3):e1010397. doi: 10.1371/journal.ppat.1010397. eCollection 2022 Mar.
Bacterial infections are a major cause of morbidity and mortality worldwide and the rise of antibiotic resistance necessitates development of alternative treatments. Pathogen adhesins that bind to host cells initiate disease pathogenesis and represent potential therapeutic targets. We have shown previously that the BspC adhesin in Group B Streptococcus (GBS), the leading cause of bacterial neonatal meningitis, interacts with host vimentin to promote attachment to brain endothelium and disease development. Here we determined that the BspC variable (V-) domain contains the vimentin binding site and promotes GBS adherence to brain endothelium. Site directed mutagenesis identified a binding pocket necessary for GBS host cell interaction and development of meningitis. Using a virtual structure-based drug screen we identified compounds that targeted the V-domain binding pocket, which blocked GBS adherence and entry into the brain in vivo. These data indicate the utility of targeting the pathogen-host interface to develop anti-virulence therapeutics.
细菌感染是全球发病率和死亡率的主要原因，抗生素耐药性的上升需要开发替代疗法。与宿主细胞结合的病原体黏附素引发疾病发病机制，代表潜在的治疗靶点。我们之前已经表明，B 组链球菌 (GBS) 中的 BspC 黏附素是细菌性新生儿脑膜炎的主要原因，与宿主波形蛋白相互作用，促进与脑内皮细胞的附着和疾病的发展。在这里，我们确定 BspC 可变 (V-) 结构域包含波形蛋白结合位点，并促进 GBS 附着于脑内皮细胞。定点突变确定了与 GBS 宿主细胞相互作用和脑膜炎发展相关的必需结合口袋。使用基于虚拟结构的药物筛选，我们鉴定了靶向 V 结构域结合口袋的化合物，该化合物可阻断 GBS 的附着和体内进入大脑。这些数据表明靶向病原体-宿主界面开发抗毒力治疗的有效性。
