Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Antimicrob Agents Chemother. 2012 Apr;56(4):1921-30. doi: 10.1128/AAC.06372-11. Epub 2012 Jan 30.
We describe the molecular mode of action and pharmacodynamics of a new molecular entity (NME) that induces the NLRP3 inflammasome-mediated innate immune response. This innate response reduces the pathogen load in an experimentally induced methicillin-resistant Staphylococcos aureus infection, enhances survival in an experimentally induced Gram-negative bacteremia, and overrides the escape mechanism of an obligate intracellular pathogen, viz. Chlamydia pneumoniae. Furthermore, the NME is more effective than standard-of-care antibiotic therapy in a clinically established multifactorial bacterial infection. Analysis of transcriptional regulation of inflammasome signaling genes and innate/adaptive immune genes revealed consistent and significant host changes responsible for the improved outcomes in these infections. These studies pave the way for the development of first-in-class drugs that enhance inflammasome-mediated pathogen clearance and identify the NLRP3 inflammasome as a drug target to address the global problem of emerging new infectious diseases and the reemergence of old diseases in an antibiotic-resistant form.
我们描述了一种新型分子实体（NME）的分子作用模式和药效动力学，该分子实体诱导 NLRP3 炎性体介导的先天免疫反应。这种先天反应可减少实验性诱导的耐甲氧西林金黄色葡萄球菌感染中的病原体负荷，提高实验性诱导的革兰氏阴性菌血症的存活率，并克服专性细胞内病原体衣原体的逃逸机制。此外，在临床确立的多因素细菌感染中，NME 比标准护理抗生素治疗更有效。对炎性体信号基因和先天/适应性免疫基因的转录调控分析揭示了一致且显著的宿主变化，这些变化是这些感染中改善结果的原因。这些研究为开发增强炎性体介导的病原体清除的首创类药物铺平了道路，并确定 NLRP3 炎性体作为药物靶点，以解决新兴新传染病和以抗生素耐药形式重新出现的旧疾病的全球问题。
