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| 2. |
- Wang, Dai, et al.
(författare)
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Identification of bacterial target proteins for the salicylidene acylhydrazide class of virulence blocking compounds
- 2011
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 286:34, s. 29922-29931
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Tidskriftsartikel (refereegranskat)abstract
- A class of anti-virulence compounds, the salicylidene acylhydrazides, have been widely reported to block the function of the type three secretion system of several Gram-negative pathogens by a previously unknown mechanism. In this work, we provide the first identification of bacterial proteins that are targeted by this group of compounds. We provide evidence that their mode of action is likely to result from a synergistic effect arising from a perturbation of the function of several conserved proteins. We also examine the contribution of selected target proteins to the pathogenicity of Yersina pseudotuberculosis and to expression of virulence genes in Escherichia coli O157.
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| 3. |
- Tree, Jai J, et al.
(författare)
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Characterization of the effects of salicylidene acylhydrazide compounds on type III secretion in Escherichia coli O157 : H7
- 2009
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Ingår i: Infection and immunity. - 1098-5522. ; 77:10, s. 4209-20
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Tidskriftsartikel (refereegranskat)abstract
- Recent work has highlighted a number of compounds that target bacterial virulence by affecting gene regulation. In this work, we show that small-molecule inhibitors affect the expression of the type III secretion system (T3SS) of Escherichia coli O157:H7 in liquid culture and when this bacterium is attached to bovine epithelial cells. Inhibition of T3SS expression resulted in a reduction in the capacity of the bacteria to form attaching and effacing lesions. Our results show that there is marked variation in the abilities of four structurally related compounds to inhibit the T3SS of a panel of isolates. Using transcriptomics, we performed a comprehensive analysis of the conserved and inhibitor-specific transcriptional responses to these four compounds. These analyses of gene expression show that numerous virulence genes, located on horizontally acquired DNA elements, are affected by the compounds, but the number of genes significantly affected varied markedly for the different compounds. Overall, we highlight the importance of assessing the effect of such "antivirulence" agents on a range of isolates and discuss the possible mechanisms which may lead to the coordinate downregulation of horizontally acquired virulence genes.
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| 4. |
- Huerta-Uribe, Alejandro, et al.
(författare)
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Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7
- 2016
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Infections caused by Shiga toxin-producing E. coli strains constitute a health problem, as they are problematic to treat. Shiga toxin (Stx) production is a key virulence factor associated with the pathogenicity of enterohaemorrhagic E. coli (EHEC) and can result in the development of haemolytic uremic syndrome in infected patients. The genes encoding Stx are located on temperate lysogenic phages integrated into the bacterial chromosome and expression of the toxin is generally coupled to phage induction through the SOS response. We aimed to find new compounds capable of blocking expression of Stx type 2 (Stx2) as this subtype of Stx is more strongly associated with human disease. High-throughput screening of a small-molecule library identified a lead compound that reduced Stx2 expression in a dose-dependent manner. We show that the optimised compound interferes with the SOS response by directly affecting the activity and oligomerisation of RecA, thus limiting phage activation and Stx2 expression. Our work suggests that RecA is highly susceptible to inhibition and that targeting this protein is a viable approach to limiting production of Stx2 by EHEC. This type of approach has the potential to limit production and transfer of other phage induced and transduced determinants.
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