Principal Investigator (PI)
The Foundation is providing £113,846 in support.
Marija Miljkovic
GSK will provide compounds for screening, consumables and expertise to perform the HTS and to select and prioritize the most promising hits. Biology and pharmacology support will be provided as well
Diarrheal diseases, such as shigellosis, are the second leading cause of death in children under five years old. Many strains of Shigella spp. are drug or multi-drug resistant. Genetic knock-out studies of the Shigella virulence pathway controlled by the AraC-family transcription factor VirF (required for infection, cell-to-cell spread and escape from macrophages) show that inactivation of VirF or other virulence factors eliminates, or significantly reduces, pathogenicity. Importantly, expression of virulence factors is not required for Shigella viability; therefore, targeting virulence factors is expected to lower the risk for resistance development in Shigella while not affecting normal, avirulent colonic microbiota. We have identified 5 hits from an HTS of ~150,000 small molecules that inhibit VirF expression of a reporter gene and reduce the invasion efficiency of Shigella in in vitro models of infection. One of these hits blocks VirF binding to DNA. Our goal in this proposal is to identify novel and potent chemical matter that block Shigella virulence to conduct a ‘hit-to-lead” campaign. We will screen compounds from GSK’s 1.7M compound library, perform confirmation and secondary assays probing mechanism of action, PK/Tox and in vitro efficacy. Compounds that inhibit VirF•DNA binding will be co-crystalized with the VirF DNA binding domain to enable a structure-based hit-to-lead campaign