title: NLRP3 inflammasome is a target for development of broad-spectrum anti-infective drugs.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA. jim_thacker@therimunex.com
authors.forename: James D
authors.initials: JD
authors.lastname: Thacker
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Balin
authors.forename: Denah M
authors.initials: DM
authors.lastname: Appelt
authors.forename: Sihem
authors.initials: S
authors.lastname: Sassi-Gaha
authors.forename: Mitali
authors.initials: M
authors.lastname: Purohit
authors.forename: Richard F
authors.initials: RF
authors.lastname: Rest
authors.forename: Carol M
authors.initials: CM
authors.lastname: Artlett
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy / Q000382:microbiology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D002690:Chlamydia Infections / Q000188:drug therapy / Q000382:microbiology; D016993:Chlamydophila pneumoniae / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D058847:Inflammasomes / Q000187:drug effects* / Q000235:genetics*; D008414:Mastitis, Bovine / Q000188:drug therapy / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016133:Polymerase Chain Reaction; D011817:Rabbits
chemical_list: D000890:Anti-Infective Agents; D002352:Carrier Proteins; D018925:Chemokines; D016207:Cytokines; D007075:Immunoglobulin M; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human