Nordihydroguaiaretic Acid (NDGA) Inhibits CsgA Polymerization, Bacterial Amyloid Biogenesis, and Biofilm Formation.
Chembiochem : a European journal of chemical biology
Escherichia coli and other Enterobacteriaceae thrive in robust biofilm communities through the coproduction of curli amyloid fibers and phosphoethanolamine cellulose. Curli promote adhesion to abiotic surfaces and plant and human host tissues and are associated with pathogenesis in urinary tract infection and foodborne illness. As amyloid, curli production in the host has also been implicated in the pathogenesis of neurodegenerative diseases. We report that the natural product nordihydroguaiaretic acid (NDGA) is effective as a curlicide in E. coli. NDGA prevents CsgA polymerization in vitro in a dose-dependent manner. NDGA selectively inhibits cellassociated curli assembly in E. coli and inhibits biofilm formation among uropathogenic E. coli in a curli-specific manner. More broadly, our work emphasizes the ability to evaluate and identify bioactive amyloid assembly inhibitors using the powerful gene-directed amyloid biogenesis machinery in E. coli.
View details for DOI 10.1002/cbic.202300266
View details for PubMedID 37195016
ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (21): e2119189119
SignificanceThe immune system strikes a careful balance between launching a robust response to threats and avoiding overactivation. The molecule cGAMP is an immunotransmitter that activates innate immunity and signals extracellularly, where it is subject to degradation by the enzyme ENPP1. Here, we engineer ENPP1 to lose activity toward cGAMP but not other substrates, thus creating a biochemically precise tool to understand how ENPP1 regulates extracellular cGAMP and thus innate immunity. We uncover that ENPP1's degradation of extracellular cGAMP has a long evolutionary history, and that this mechanism is critical for controlling diverse immune threats, including viral infection and inflammation.
View details for DOI 10.1073/pnas.2119189119
View details for PubMedID 35588451
Therapeutic Interventions Targeting Innate Immune Receptors: A Balancing Act
2022; 122 (3): 3414-3458
The innate immune system is an organism's first line of defense against an onslaught of internal and external threats. The downstream adaptive immune system has been a popular target for therapeutic intervention, while there is a relative paucity of therapeutics targeting the innate immune system. However, the innate immune system plays a critical role in many human diseases, such as microbial infection, cancer, and autoimmunity, highlighting the need for ongoing therapeutic research. In this review, we discuss the major innate immune pathways and detail the molecular strategies underpinning successful therapeutics targeting each pathway as well as previous and ongoing efforts. We will also discuss any recent discoveries that could inform the development of novel therapeutic strategies. As our understanding of the innate immune system continues to develop, we envision that therapies harnessing the power of the innate immune system will become the mainstay of treatment for a wide variety of human diseases.
View details for DOI 10.1021/acs.chemrev.1c00716
View details for Web of Science ID 000767145700008
View details for PubMedID 34870969