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Sökning: WFRF:(Marquez Rudi)

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1.
  • Huerta-Uribe, Alejandro, et al. (författare)
  • Identification and Characterization of Novel Compounds Blocking Shiga Toxin Expression in Escherichia coli O157:H7
  • 2016
  • Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 7
  • 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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2.
  • Zambelloni, Riccardo, et al. (författare)
  • Crystal structures of WrbA, a spurious target of the salicylidene acylhydrazide inhibitors of type III secretion in Gram-negative pathogens, and verification of improved specificity of next-generation compounds
  • 2022
  • Ingår i: Microbiology. - : Microbiology Society. - 1350-0872 .- 1465-2080. ; 168:7
  • Tidskriftsartikel (refereegranskat)abstract
    • The enterohemorrhagic Escherichia coli pathotype is responsible for severe and dangerous infections in humans. Establishment of the infection requires colonization of the gastro-intestinal tract, which is dependent on the Type III Secretion System. The Type III Secretion System (T3SS) allows attachment of the pathogen to the mammalian host cell and cytoskeletal rearrangements within the host cell. Blocking the functionality of the T3SS is likely to reduce colonization and therefore limit the disease. This route offers an alternative to antibiotics, and problems with the development of antibiotics resistance. Salicylidene acylhydrazides have been shown to have an inhibitory effect on the T3SS in several pathogens. However, the main target of these compounds is still unclear. Past work has identified a number of putative protein targets of these compounds, one of which being WrbA. Whilst WrbA is considered an off-target interaction, this study presents the effect of the salicylidne acylhydrazide compounds on the activity of WrbA, along with crystal structures of WrbA from Yersinia pseudotuberculosis and Salmonella serovar Typhimurium; the latter also containing parts of the compound in the structure. We also present data showing that the original compounds were unstable in acidic conditions, and that later compounds showed improved stability.
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