Salicylidene Acylhydrazides That Affect Type III Protein Secretion in<i>Salmonella enterica</i>Serovar Typhimurium

Negrea, Aurel; Bjur, Eva; Ygberg, Sofia; Elofsson, Mikael; Wolf‐Watz, Hans; Rhen, Mikael

doi:10.1128/aac.00223-07

Cited by 104 publications

(159 citation statements)

References 55 publications

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“…As TrxA is connected to SPI2 activity and virulence, we continued by examining whether these activities of TrxA were restricted to the SPI2 T3SS or whether the SPI1 or T3SS-related flagellar systems also respond to TrxA activity. The functionality of the SPI1 T3SS can be determined through monitoring SPI1 effector protein secretion in vitro and invasiveness of S. serovar Typhimurium bacteria in cell culture-based infection assays (14,39,43,49). To probe for a possible role of TrxA in SPI1 activity, we set out to isolate and analyze SPI1 effector proteins secreted by wild-type S. serovar Typhimurium and its isogenic trxA mutant under SPI1-inducing growth conditions.…”

Section: Spi2mentioning

confidence: 99%

Thioredoxin 1 Participates in the Activity of theSalmonella entericaSerovar Typhimurium Pathogenicity Island 2 Type III Secretion System

et al. 2009

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The facultative intracellular pathogen Salmonella enterica serovar Typhimurium relies on its Salmonella pathogenicity island 2 (SPI2) type III secretion system (T3SS) for intracellular replication and virulence. We report that the oxidoreductase thioredoxin 1 (TrxA) and SPI2 are coinduced for expression under in vitro conditions that mimic an intravacuolar environment, that TrxA is needed for proper SPI2 activity under these conditions, and that TrxA is indispensable for SPI2 activity in both phagocytic and epithelial cells. Infection experiments in mice demonstrated that SPI2 strongly contributed to virulence in a TrxA-proficient background whereas SPI2 did not affect virulence in a trxA mutant. Complementation analyses using wild-type trxA or a genetically engineered trxA coding for noncatalytic TrxA showed that the catalytic activity of TrxA is essential for SPI2 activity in phagocytic cells whereas a noncatalytic variant of TrxA partially sustained SPI2 activity in epithelial cells and virulence in mice. These results show that TrxA is needed for the intracellular induction of SPI2 and provide new insights into the functional integration between catalytic and noncatalytic activities of TrxA and a bacterial T3SS in different settings of intracellular infections.

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Section: Spi2mentioning

confidence: 99%

Thioredoxin 1 Participates in the Activity of theSalmonella entericaSerovar Typhimurium Pathogenicity Island 2 Type III Secretion System

et al. 2009

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“…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. 19 We have isolated new compounds, guadinomines, produced by Streptomyces sp.…”

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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“…The second is that a recently discovered class of type III secretion inhibitor can block secretion in multiple species-Y. pestis, Chlamydia trachomatis, and Salmonella enterica serovar Typhimurium (5,29,45,48,53)-though the mechanism of inhibition is unclear (48). It has been shown from available structures of effectors bound to their cognate chaperones that the structure of this interaction is conserved across species (39).…”

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Computational Prediction of Type III and IV Secreted Effectors in Gram-Negative Bacteria

et al. 2011

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In this review, we provide an overview of the methods employed in four recent studies that described novel methods for computational prediction of secreted effectors from type III and IV secretion systems in Gramnegative bacteria. We present the results of these studies in terms of performance at accurately predicting secreted effectors and similarities found between secretion signals that may reflect biologically relevant features for recognition. We discuss the Web-based tools for secreted effector prediction described in these studies and announce the availability of our tool, the SIEVE server (http://www.sysbep.org/sieve). Finally, we assess the accuracies of the three type III effector prediction methods on a small set of proteins not known prior to the development of these tools that we recently discovered and validated using both experimental and computational approaches. Our comparison shows that all methods use similar approaches and, in general, arrive at similar conclusions. We discuss the possibility of an order-dependent motif in the secretion signal, which was a point of disagreement in the studies. Our results show that there may be classes of effectors in which the signal has a loosely defined motif and others in which secretion is dependent only on compositional biases. Computational prediction of secreted effectors from protein sequences represents an important step toward better understanding the interaction between pathogens and hosts.

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Salicylidene Acylhydrazides That Affect Type III Protein Secretion inSalmonella entericaSerovar Typhimurium

Cited by 104 publications

References 55 publications

Thioredoxin 1 Participates in the Activity of theSalmonella entericaSerovar Typhimurium Pathogenicity Island 2 Type III Secretion System

Thioredoxin 1 Participates in the Activity of theSalmonella entericaSerovar Typhimurium Pathogenicity Island 2 Type III Secretion System

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

Computational Prediction of Type III and IV Secreted Effectors in Gram-Negative Bacteria

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