An Inhibitor of Gram-Negative Bacterial Virulence Protein Secretion

Felise, Heather B.; Nguyen, Hai Vu; Pfuetzner, Richard A.; Barry, Kathleen C.; Jackson, Stona R.; Blanc, Marie Pierre; Bronstein, Philip A.; Kline, Toni; Miller, Samuel I.

doi:10.1016/j.chom.2008.08.001

Cited by 156 publications

(174 citation statements)

References 45 publications

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“…Active phospholipase has the ability to cleave specific substrates, and such cleavage results can be measured using a fluorometer. 19 Many derivatives, including salicylidene acylhydrazide and 2-imino-5-arylidene thiazolidinone, have already been developed. Such compounds are known to inhibit T3SS function in Chlamydia, EHEC O157, Salmonella and Yersinia, but they have not yet been evaluated in vivo.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…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. K01-0509 as T3SS inhibitors of EPEC.…”

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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“…From the perspective of potential drug development, it is interesting that much recent interest has focused on the targeting of virulence mechanisms (5,18,29). Nonetheless, approaches based on inhibiting virulence will likely suffer from a limited spectrum, as most proteins that contribute to virulence are not essential and thus free to diverge.…”

Section: Discussionmentioning

confidence: 99%

Type I Signal Peptidase and Protein Secretion inStaphylococcus epidermidis

et al. 2011

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Bacterial protein secretion is a highly orchestrated process that is essential for infection and virulence. Despite extensive efforts to predict or experimentally detect proteins that are secreted, the characterization of the bacterial secretome has remained challenging. A central event in protein secretion is the type I signal peptidase (SPase)-mediated cleavage of the N-terminal signal peptide that targets a protein for secretion via the general secretory pathway, and the arylomycins are a class of natural products that inhibit SPase, suggesting that they may be useful chemical biology tools for characterizing the secretome. Here, using an arylomycin derivative, along with two-dimensional gel electrophoresis and liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identify 11 proteins whose secretion from stationary-phase Staphylococcus epidermidis is dependent on SPase activity, 9 of which are predicted to be translated with canonical N-terminal signal peptides. In addition, we find that the presence of extracellular domains of lipoteichoic acid synthase (LtaS) and the ␤-lactam response sensor BlaR1 in the medium is dependent on SPase activity, suggesting that they are cleaved at noncanonical sites within the protein. In all, the data define the proteins whose stationaryphase secretion depends on SPase and also suggest that the arylomycins should be valuable chemical biology tools for the study of protein secretion in a wide variety of different bacteria.

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“…1). Inhibitors of the Salmonella enterica serovar Typhimurium T3SS were identified using a reporter strain that secretes phospholipase in a T3SS-dependent manner (16). This phenotypic approach to cell-based screening can result in hits that affect any of several steps in production of a functional phospholipase, including transcription, translation, protein folding, protein-protein interaction, and translocation.…”

Section: Small Molecules That Affect Virulence Factors and Their Regumentioning

confidence: 99%

Chemical Biology Applied to the Study of Bacterial Pathogens

Anthouard

DiRita

2015

Infect Immun

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In recent years, chemical biology and chemical genomics have been increasingly applied to the field of microbiology to uncover new potential therapeutics as well as to probe virulence mechanisms in pathogens. The approach offers some clear advantages, as identified compounds (i) can serve as a proof of principle for the applicability of drugs to specific targets; (ii) can serve as conditional effectors to explore the function of their targets in vitro and in vivo; (iii) can be used to modulate gene expression in otherwise genetically intractable organisms; and (iv) can be tailored to a narrow or broad range of bacteria. This review highlights recent examples from the literature to illustrate how the use of small molecules has advanced discovery of novel potential treatments and has been applied to explore biological mechanisms underlying pathogenicity. We also use these examples to discuss practical considerations that are key to establishing a screening or discovery program. Finally, we discuss the advantages and challenges of different approaches and the methods that are emerging to address these challenges.

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An Inhibitor of Gram-Negative Bacterial Virulence Protein Secretion

Cited by 156 publications

References 45 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

Type I Signal Peptidase and Protein Secretion inStaphylococcus epidermidis

Chemical Biology Applied to the Study of Bacterial Pathogens

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