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

Document Type

Article

Publication Date

4-1-2012

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.

Publication Title

Antimicrobial Agents and Chemotherapy

Volume

56

Issue

4

First Page

1921

Last Page

1930

PubMed ID

22290938

Comments

This article was published in Antimicrobial Agents and Chemotherapy, Volume 56 Issue 4, April 2012, pages 1921-1930

The published version is available at http://dx.doi.org/10.1128/AAC.06372-11

Copyright © 2012, American Society for Microbiology.

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