NLRP3 Inflammasome Is a Target for Development of Broad-Spectrum Anti-Infective Drugs

作者：Thacker James D^*; Balin Brian J; Appelt Denah M; Sassi Gaha Sihem; Purohit Mitali; Rest Richard F; Artlett Carol M

来源：Antimicrobial Agents and Chemotherapy, 2012, 56(4): 1921-1930.

DOI：10.1128/AAC.06372-11

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.

• 出版日期2012-4