Salicylanilides are Potent Inhibitors of Type III Secretion in Yersinia

Kauppi, Anna M.; Nordfelth, Roland; Hägglund, Ulrik; Wolf‐Watz, Hans; Elofsson, Mikael

doi:10.1007/0-306-48416-1_17

Cited by 29 publications

(31 citation statements)

References 7 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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The type III secretion system (T3SS) is highly conserved in many Gram-negative pathogenic bacteria and functions as an injector of bacterial proteins (effectors) into host cells. T3SSs are involved in establishing disease processes, but this machinery is not essential for bacterial growth or homeostasis. Thus, T3SS is expected to be a candidate therapeutic target, and inhibitors of T3SSs could potentially reduce virulence without causing bacterial death, thereby avoiding any subsequent development of resistance. We identified a linear polyketide compound, aurodox, as a specific T3SS inhibitor from the culture broth of Streptomyces sp. using a screening system for the T3SS-mediated hemolysis of enteropathogenic Escherichia coli (EPEC) established by our group. Aurodox strongly inhibited T3SS-mediated hemolysis with an IC 50 value of 1.5 lg ml À1 without affecting bacterial growth in liquid media. We also demonstrated that aurodox specifically inhibits the secretion of type IIIsecreted proteins such as EspB, EspF and Map, without affecting the expression of the housekeeping protein GroEL. Furthermore, an in vivo infection study using mice clearly indicated that the administration of aurodox allowed the mice to survive a lethal dose of Citrobactor rodentium, a model bacterium for human pathogens such as EPEC. Thus, our in vivo study directly demonstrated for the first time that this putative T3SS inhibitor can be applied as a novel class of anti-infective agents.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…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).…”

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confidence: 99%

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confidence: 99%

Small-Molecule Inhibitors Specifically Targeting Type III Secretion

Nordfelth¹,

Kauppi

Norberg³

et al. 2005

Infect Immun

190

223

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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...

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“…T3SS proteins are attractive targets for 'anti-virulence' compounds because they are often essential to the virulence of widely distributed Gram-negative bacterial pathogens of plants, animals and humans. Recently, whole-cell-based high-throughput screens have been performed to identify T3SS inhibitors and have identified several classes of small-molecule compounds (salicylidene acylhydrazides, salicylanilides, sulfonylaminobenzanilides, benzimidazoles and a thiazolidinone) and three natural products as effective agents against a number of pathogenic bacteria that utilize the T3SS, including Yersinia, Chlamydia, Salmonella, enteropathogenic Escherichia coli and Shigella (Kauppi et al, 2003;Pan et al, 2007;Grier et al, 2010;Garrity-Ryan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis

Zigangirova

Kost

Didenko

et al. 2016

Journal of Medical Microbiology

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A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis Chlamydia trachomatis is one of the most common sexually transmitted pathogens in the world and often causes chronic inflammatory diseases that are insensitive to antibiotics. The type 3 secretion system (T3SS) of pathogenic bacteria is a promising target for therapeutic intervention aimed at bacterial virulence and can be an attractive alternative for the treatment of chronic infections. Recently, we have shown that a small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones produced through the chemical modification of the thiohydrazides of oxamic acids, designated CL-55, inhibited the intracellular growth of C. trachomatis in a T3SS-dependent manner. To assess the feasibility of CL-55 as a therapeutic agent, our aim was to determine which point(s) in the developmental cycle CL-55 affects. We found that CL-55 had no effect on the adhesion of elementary bodies (EBs) to host cells but significantly suppressed EB internalization. We further found that CL-55 inhibited the intracellular division of reticulate bodies (RBs). An ultrastructural analysis revealed loss of contact between the RBs and the inclusion membrane in the presence of CL-55. Finally, we found that our T3SS inhibitor prevented the persistence of Chlamydia in cell culture and its reversion to the infectious state. Our findings indicate that our T3SS inhibitor may be effective in the treatment of both productive and persistent infections.

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Salicylanilides are Potent Inhibitors of Type III Secretion in Yersinia

Cited by 29 publications

References 7 publications

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

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

Small-Molecule Inhibitors Specifically Targeting Type III Secretion

A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones inhibits intracellular growth and persistence of Chlamydia trachomatis

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