Small-Molecule Inhibitors Specifically Targeting Type III Secretion

Abstract

The type III secretion (TTS) system is used by several animal and plant pathogens to deliver effector proteins into the cytosol of the eukaryotic target cell as a strategy to evade the defense reactions elicited by the infected organism. The fact that these systems are highly homologous implies that novel antibacterial agents that chemically attenuate the pathogens via a specific interaction with the type III secretion mechanism can be identified. Type III secretion (TTS) constitutes a common virulence system present in many gram-negative species, including Yersinia spp., Salmonella spp., Shigella spp., Pseudomonas aeruginosa, entheropathogenic Escherichia coli, enterohemoragic E. coli, and Chlamydia spp. (11,24). The bacteria depend on their respective TTS system to invade the host, resist phagocytosis, grow in deep tissues, and cause disease. Furthermore, studies have revealed that several components of the TTS systems are conserved between different species (11, 42). These findings offer a possibility to develop novel antibacterial agents that target TTS-based virulence (32, 50). Moreover, small molecules that interfere with TTS can be utilized as tools in efforts aiming at increasing our understanding of complex bacterial virulence systems by using a chemical genetics approach (29,50). The strategy of identifying and using small molecules in functional studies of microbial virulence is attractive and complements current methods in the field, as illustrated by some recent publications (7,26,27,47).The well-studied, 70-kb-plasmid-encoded Ysc (for Yersinia secretion) TTS system of Yersinia (51) represents a suitable target for both drug development (32) and a small-molecule approach to address protein function (50). Of the 11 known species of Yersinia, Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis are pathogenic to mammals (51). The Ysc TTS apparatus is essential for the bacteria to evade the host immune defense, and compounds targeting this mechanism will result in attenuation without affecting bacterial growth. Interestingly 10 of the Ysc proteins have counterparts in almost all TTS systems, and it has been shown that some components of the secretion systems are interchangeable among different species (20), demonstrating evolutionary conservation. Since the TTS systems are conserved among the gram-negative bacteria utilizing this virulence mechanism it is likely that compounds targeting TTS machinery in Yersinia will also affect the TTS system in other species and that data generated with one species would also be valid for others. The importance of TTS studies is further stressed by the fact that the number of multiresistant strains in different species that utilize this virulence system is rising (38). Moreover, multiresistant strains of Y. pestis, a potential weapon in biological warfare and bioterrorism (25), have been isolated (18).During the progress of an infection the Yersinia bacterium adheres to eukaryotic cells, e.g., macrophages, and injects a set of effector proteins, called Yops (for Y...

A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

“…A class of acylated hydrazones was recently identified that inhibited TTS of Y. pseudotuberculosis without affecting the in vitro growth rate (2,3). The same class of compounds has also been shown to inhibit TTS of Pseudomonas aeruginosa as well as S. typhimurium (unpublished data), suggesting that these compounds target the secretory apparatus itself rather than individual effector molecules.…”

A small-molecule inhibitor of the bacterial type III secretion system protects against in vivo infection with Citrobacter rodentium

“…Caminosides, unique glycolipids, were isolated from the marine sponge Caminus sphaeroconia in a screen system in which Esp proteins, secreted from EPEC, were detected by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). 9 Salicylidene acylhydrazide compounds inhibit the functioning of T3SS in Yersinia, 10,11 Chlamydia, 12-14 Shigella, 15 EHEC 16 and Salmonella. 17,18 Furthermore, 2-imino-5-arylidene thiazolidinone inhibits T3SS function at the transcriptional level in Salmonella and in a plant pathogen, Pseudomonas syringae.…”

Virstatin inhibits dimerization of the transcriptional activator ToxT

“…These efforts have laid the groundwork for a new class of antibiotics that target regulation of these virulence mechanisms. Several recent reports have described the identification of many such drugs, including inhibitors of type III secretion, quorum sensing, and toxin activity (1)(2)(3)(4)(5)(6)(7).…”