Laboratory of Theoretical and Computational Chemistry, International Joint Research Laboratory Nano-Micro Architecture Chemistry, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Theoretical Chemistry, Institute of Zoonosis, College of Veterinary Medicine, Department of Infectious Diseases, First Hospital of Jilin University, Jilin University, Changchun, China.
Key Lab for New Drugs Research of TCM in Shenzhen, Research Institute of Tsinghua University in Shenzhen, Shenzhen, China.
Front Cell Infect Microbiol. 2019 Jul 15;9:253. doi: 10.3389/fcimb.2019.00253. eCollection 2019.
α-Hemolysin (Hla) is a significant virulence factor in ()-caused infectious diseases such as pneumonia. Thus, to prevent the production of Hla when treating infection, it is necessary to choose an antibiotic with good antibacterial activity and effect. In our study, we observed that Fosfomycin (FOM) at a sub-inhibitory concentration inhibited expression of Hla. Molecular dynamics demonstrated that FOM bound to the binding sites LYS 154 and ASP 108 of Hla, potentially inhibiting Hla. Furthermore, we verified that staphylococcal membrane-derived vesicles (SMVs) contain Hla and that FOM treatment significantly reduced the production of SMVs and Hla. Based on our pharmacological inhibition analysis, ERK and p38 activated NLRP3 inflammasomes. Moreover, FOM inhibited expression of MAPKs and NLRP3 inflammasome-related proteins in as well as SMV-infected human macrophages (MΦ) and alveolar epithelial cells. , SMVs isolated from DU1090 (an isogenic Hla deletion mutant) or the strain itself caused weaker inflammation than that of its parent strain 8325-4. FOM also significantly reduced the phosphorylation levels of ERK and P38 and expression of NLRP3 inflammasome-related proteins. In addition, FOM decreased MPO activity, pulmonary vascular permeability and edema formation in the lungs of mice with -caused pneumonia. Taken together, these data indicate that FOM exerts protective effects against infection and by inhibiting Hla in SMVs and blocking ERK/P38-mediated NLRP3 inflammasome activation by Hla.
α-溶血素（Hla）是引起肺炎等感染性疾病的重要毒力因子。因此，在治疗感染时，为了防止 Hla 的产生，需要选择具有良好抗菌活性和效果的抗生素。在我们的研究中，我们观察到亚抑菌浓度的磷霉素（FOM）抑制 Hla 的表达。分子动力学表明，FOM 结合到 Hla 的结合位点 LYS154 和 ASP108，可能抑制 Hla。此外，我们验证了葡萄球菌膜衍生小泡（SMVs）含有 Hla，并且 FOM 处理显著减少了 SMVs 和 Hla 的产生。基于我们的药理学抑制分析，ERK 和 p38 激活 NLRP3 炎性体。此外，FOM 抑制了 MAPKs 和 NLRP3 炎性体相关蛋白在和 SMV 感染的人巨噬细胞（MΦ）和肺泡上皮细胞中的表达。有趣的是，从 DU1090（同源 Hla 缺失突变体）或其自身分离的 SMVs 引起的炎症比其亲本菌株 8325-4 弱。FOM 还显著降低了 ERK 和 P38 的磷酸化水平以及 NLRP3 炎性体相关蛋白的表达。此外，FOM 降低了肺炎链球菌引起的肺炎小鼠肺部的髓过氧化物酶（MPO）活性、肺血管通透性和水肿形成。总之，这些数据表明，FOM 通过抑制 SMVs 中的 Hla 和阻断 Hla 介导的 ERK/P38-NLRP3 炎性体激活，发挥对感染和的保护作用。
