Principal Investigator (PI)
The Foundation is providing £131,383 in support.
Milka Hammaren
GSK will provide expertise with high throughput screening set ups and compound screening, as well as with data analysis. GSK will provide compound libraries and drug discovery expertise to assist in the compound selection. Materials for the experimental part performed at GSK will be provided in kind. GSK pharmacologist experts will support this project to unravel the PK/PD of synergistic combinations.
Combinatorial treatments provide an untapped, cost-effective source for new antibacterial treatments at a time where new therapies are urgently needed. Here we propose to establish a high-content microscopy platform for systematically screening drug combinations against intracellular Shigella. Shigellosis is one of the leading causes of diarrhea worldwide, with infections being more frequent and deadly in the developing world. The microscopy platform set up will not only facilitate high-throughput screening at the intracellular context of infection, where this pathogen has to be targeted, but will also provide insights into the mechanism-of-action of single drug(s) and the combinatorial treatment by monitoring the stage of infection and the host process(es) they affect. Using this platform, we will evaluate the impact of ~5,000 drug combinations during the course of infection in epithelial cells and macrophages. Strong synergies will be further evaluated in detailed surface response measurements (inhibition and killing curves – intracellularly and extracellularly), resistant and persistent assays. Last, prominent candidates will be moved to animal models and PK/PD measurements.