Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces sp. K01-0509

Iwatsuki, Masato; Uchida, Ryuji; Yoshijima, Hitomi; Ui, Hideaki; Shiomi, Kazuro; Kim, Yong-Pil; Hirose, Tomoyasu; Sunazuka, Toshiaki; Abe, Akio; Tomoda, Hiroshi; Ōmura, Satoshi

doi:10.1038/ja.2008.33

Cited by 44 publications

(38 citation statements)

References 11 publications

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“…The current strategies for targeting Yersinia pestis and other type III secretion system-utilizing pathogens rely mostly on phenotypic screens [3], [9], [48], [49], [50], [51], [52]. The strategy uses a library of random compounds or a smaller set of molecules and the readout is a blockage of secretion of a defined substrate into the host.…”

Section: Discussionmentioning

confidence: 99%

Identification of Small-Molecule Inhibitors of Yersinia pestis Type III Secretion System YscN ATPase

et al. 2011

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Yersinia pestis is a Gram negative zoonotic pathogen responsible for causing bubonic and pneumonic plague in humans. The pathogen uses a type III secretion system (T3SS) to deliver virulence factors directly from bacterium into host mammalian cells. The system contains a single ATPase, YscN, necessary for delivery of virulence factors. In this work, we show that deletion of the catalytic domain of the yscN gene in Y. pestis CO92 attenuated the strain over three million-fold in the Swiss-Webster mouse model of bubonic plague. The result validates the YscN protein as a therapeutic target for plague. The catalytic domain of the YscN protein was made using recombinant methods and its ATPase activity was characterized in vitro. To identify candidate therapeutics, we tested computationally selected small molecules for inhibition of YscN ATPase activity. The best inhibitors had measured IC50 values below 20 µM in an in vitro ATPase assay and were also found to inhibit the homologous BsaS protein from Burkholderia mallei animal-like T3SS at similar concentrations. Moreover, the compounds fully inhibited YopE secretion by attenuated Y. pestis in a bacterial cell culture and mammalian cells at µM concentrations. The data demonstrate the feasibility of targeting and inhibiting a critical protein transport ATPase of a bacterial virulence system. It is likely the same strategy could be applied to many other common human pathogens using type III secretion system, including enteropathogenic E. coli, Shigella flexneri, Salmonella typhimurium, and Burkholderia mallei/pseudomallei species.

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Section: Discussionmentioning

confidence: 99%

Identification of Small-Molecule Inhibitors of Yersinia pestis Type III Secretion System YscN ATPase

et al. 2011

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“…A screen in Yersinia by Harmon et al (83) identified various chemically diverse hydrophobic compounds that inhibited translocation of effectors into eukayrotic cells, but not in vitro secretion or expression, suggesting they disrupted the formation of a functional translocon or that they inhibited interaction with the host cell. Various compounds showing inhibition of T3SS-mediated hemolysis, such as aurodox and the gaudinomines, have also been identified (84, 85). Other compounds, such as salicylanilides, salicylideneanilines, sulfonylaminobenzanilides, cytosporone B, and citrus flavonoids are hypothesized to broadly inhibit T3SS gene transcription through unknown mechanisms (53, 64, 86–88).…”

Section: Literature Of T3ss Inhibitorsmentioning

confidence: 99%

The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

McShan

Guzman

2014

Chem Biol Drug Des

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Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram-negative bacteria. The T3SS consists of structural proteins, effectors and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non-infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design.

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“…In recent years, whole-cell based high-throughput screens have been performed to identify inhibitors of T3SSs [5], [6], [7], [8], [9], [10]. These screens have identified several classes of synthetic compounds (salicylidene acylhydrazides, salicylanilides, sulfonylaminobenzanilides, benzimidazoles and a thiazolidinone) and three natural products (glycolipid caminosides, guadinomines and the linear polyketide antibiotic aurodox at concentrations not affecting bacterial viability) as active for inhibition of T3SSs in a range of Gram negative bacterial pathogens, including Yersinia , Chlamydia , and Salmonella [5], [6], [7], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21].…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that its target is an outer membrane component conserved between these two types of secretion system but not found in flagellar biogenesis ones [7]. The other T3SS inhibitors, including all identified natural products [12], [13], [19], [21] have unknown targets [8], [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Isolation of Salmonella Mutants Resistant to the Inhibitory Effect of Salicylidene acylhydrazides on Flagella-Mediated Motility

et al. 2013

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Salicylidene acylhydrazides identified as inhibitors of virulence-mediating type III secretion systems (T3SSs) potentially target their inner membrane export apparatus. They also lead to inhibition of flagellar T3SS-mediated swimming motility in Salmonella enterica serovar. Typhimurium. We show that INP0404 and INP0405 act by reducing the number of flagella/cell. These molecules still inhibit motility of a Salmonella ΔfliH-fliI-fliJ/flhB (P28T) strain, which lacks three soluble components of the flagellar T3S apparatus, suggesting that they are not the target of this drug family. We implemented a genetic screen to search for the inhibitors' molecular target(s) using motility assays in the ΔfliH-fliI/flhB (P28T) background. Both mutants identified were more motile than the background strain in the absence of the drugs, although HM18 was considerably more so. HM18 was more motile than its parent strain in the presence of both drugs while DI15 was only insensitive to INP0405. HM18 was hypermotile due to hyperflagellation, whereas DI15 was not hyperflagellated. HM18 was also resistant to a growth defect induced by high concentrations of the drugs. Whole-genome resequencing of HM18 indicated two alterations within protein coding regions, including one within atpB, which encodes the inner membrane a-subunit of the FOF1-ATP synthase. Reverse genetics indicated that the alteration in atpB was responsible for all of HM18's phenotypes. Genome sequencing of DI15 uncovered a single A562P mutation within a gene encoding the flagellar inner membrane protein FlhA, the direct role of which in mediating drug insensitivity could not be confirmed. We discuss the implications of these findings in terms of T3SS export apparatus function and drug target identification.

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Guadinomines, Type III Secretion System Inhibitors, Produced by Streptomyces sp. K01-0509

Cited by 44 publications

References 11 publications

Identification of Small-Molecule Inhibitors of Yersinia pestis Type III Secretion System YscN ATPase

Identification of Small-Molecule Inhibitors of Yersinia pestis Type III Secretion System YscN ATPase

The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

Isolation of Salmonella Mutants Resistant to the Inhibitory Effect of Salicylidene acylhydrazides on Flagella-Mediated Motility

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