Shigella is a facultative intracellular pathogen causing human bacillary dysentery, also known as shigellosis, an acute infection of the large intestine. The primary regulator of the virulence phenotype is VirF, a DNA-binding protein belonging to the AraC family of transcriptional regulators. The virF gene, located on a large virulence plasmid (pINV), is expressed only within the host, mainly in response to the temperature transition occurring when the bacterium transits from the outer environment to the intestinal milieu. Like other members of the AraC family, VirF has a conserved, carboxy-terminal DNA-binding domain with two helix-turn-helix (HTH) motifs, while the N - terminal domain of VirF promotes dimerization. Recent bioinformatics analyses have shown that VirF protein has a ¿Jelly roll¿ motif, a protein fold containing a binding pocket enclosed. This suggests a mechanism by which still unidentified molecules can interact with VirF and thus influence its activity. Previously published results about a similar protein suggest that the compounds involved in this interaction could be intestinal metabolites that contribute to the programmed expression of the virulence system within the host. The characterization and identification of these molecules may pave the way for the development of antivirulence compounds as therapeutic agents in the treatment of shigellosis.
Shigella is a highly adapted human pathogen, mainly found in the developing world and causing a severe enteric syndrome. Recent studies aim to develop new treatment strategies that inhibit virulence rather than bacterial viability, as this is considered a highly effective approach to combat bacterial infections by minimizing the emergence of antibiotic resistance (Rasko and Sperandio 2010). For this reason, VirF is considered a promising antivirulence target as its silencing prevents Shigella from invading host epithelial cells. The identification of molecules interacting with the VirF protein will improve the knowledge of the post-translational regulation of this primary regulator and provide a basis for the development of antivirulence compounds as therapeutic agents in the treatment of shigellosis.
Furthermore, the growing number of araC-like activators that share the presence of a Jelly roll module and that play an important role in the virulence of many pathogens (Yang et al., 2011), encourages research in this field aimed at identifying a single or set of compounds capable of inhibiting the activity of many regulators belonging to the AraC family of transcriptional activators (AFTR) plus gelatin at the same time, thus extending the range of applicability of these putative drugs.
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Yang J, et al., Trends Microbiol. 2011 Mar;19(3):128-35.