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: James D Thacker, Brian J Balin, Denah M Appelt, Sihem Sassi-Gaha, Mitali Purohit, Richard F Rest, Carol M Artlett
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 4 Pg. 1921-30 (Apr 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22290938 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Carrier Proteins
• Chemokines
• Cytokines
• Immunoglobulin M
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human

Topics

• Animals
• Anti-Infective Agents (pharmacology)
• Carrier Proteins (drug effects, genetics)
• Cattle
• Cattle Diseases (drug therapy, microbiology)
• Cells, Cultured
• Chemokines (biosynthesis)
• Chlamydia Infections (drug therapy, microbiology)
• Chlamydophila pneumoniae (drug effects)
• Cytokines (biosynthesis)
• Gene Expression (drug effects)
• Humans
• Immunoglobulin M (biosynthesis)
• Inflammasomes (drug effects, genetics)
• Mastitis, Bovine (drug therapy, microbiology)
• Methicillin-Resistant Staphylococcus aureus (drug effects)
• Mice
• Monocytes (drug effects, microbiology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Polymerase Chain Reaction
• Rabbits