Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates

Abstract

Traditional Chinese Medicines (TCMs) have been historically used to treat bacterial infections. However, the molecules responsible for these anti-infective properties and their potential mechanisms of action have remained elusive. Using a high-throughput assay for type III protein secretion in Salmonella enterica serovar Typhimurium, we discovered that several TCMs can attenuate this key virulence pathway without affecting bacterial growth. Amongst the active TCMs, we discovered that baicalein, a specific flavonoid from Scutellaria baicalensis, targets S. Typhimurium pathogenicity island-1 (SPI-1) type III secretion system (T3SS) effectors and translocases to inhibit bacterial invasion of epithelial cells. Structurally related flavonoids present in other TCMs, such as quercetin also inactivated the SPI-1 T3SS and attenuated S. Typhimurium invasion. Our results demonstrate that specific plant metabolites from TCMs can directly interfere with key bacterial virulence pathways and reveals a previously unappreciated mechanism of action for anti-infective medicinal plants.

In Situ Molecular Architecture of the Salmonella Type III Secretion Machine

“…and Yersinia spp. Therefore, these systems are quickly emerging as prime targets for the development of new-generation anti-infective drugs (Charro and Mota, 2015; Gu et al, 2015; Tsou et al, 2016). The type III secretion machine (or injectisome) is a complex multi-protein assembly composed of an envelope-embedded structure known as the needle complex (NC) (Kubori et al, 1998), an inner membrane export apparatus (Wagner et al, 2010), and a cytoplasmic platform that energizes the secretion process and selects and sorts substrates for their orderly delivery to the secretion machine (Lara-Tejero et al, 2011) (Fig.…”

Visualization and characterization of individual type III protein secretion machines in live bacteria

“…These machines play an essential role in the pathogenic or symbiotic relationships between the bacteria that encode them and their respective hosts. Consequently, type III secretion systems are rapidly emerging as targets for the development of novel therapeutic and prevention strategies with the potential to combat several important infectious diseases (3)(4)(5). The components of type III secretion machines are highly conserved across bacterial species although the effector proteins that they deliver are customized for the specific bacteria that harbor them (1,6,7).…”

Epigallocatechin-3-gallate inhibits bacterial virulence and invasion of host cells

“…As epigallocatechin gallate (EGCG) is the major polyphenolic components among the tea derived catechins, we compared the activities of EGCG and ECG with previously reported T3SS inhibitors baicalein 12 and INP0007 19 on endogenously secreted SPI-1 T3SS effectors from the growth media of S. Typhimurium (Fig. 1C).…”

“…12 Based on these initial findings, we explored additional plant metabolites from other medicinal and dietary sources with proposed anti-infective activities towards Gram-negative bacterial pathogens. Here we show that epigallocatechin-3-gallate (EGCG), a major metabolite from green tea, 17 a previously reported inhibitor of α-synuclein amyloid formation 13, 14 and hepatitis C viral entry 15, 16 , also effectively inhibits S. Typhimurium T3SS and invasion of host cells.…”