Innovative treatments for septicemia – Septiscreen

The incidence of sepsis is continually increasing, with 300 cases per 100,000 per year in the US. Mortality is still in the order of 30-50% resulting in 800,000 deaths per year in the US. In most cases the pathogens involved are sensitive to commonly used antibiotics but treatment is insufficient due to host factors including massive inflammation, microvasculature dysfunction and vascular leak, among others. A central assumption of this project is that there is a necessity for drugs targeting these host responses to complement antibiotic treatment. We reason that once an infection has reached a certain threshold, bacterial killing by antibiotics is restricted by biofilm-like resistance mechanisms and that furthermore, bacterial killing is not sufficient to prevent the adverse effects of infection on blood vessels. The strategy of this project is to perform a pharmacological screen to find molecular entities targeting the host pathways/receptors that block the pathogenic interaction of bacteria with the endothelium: bacterial colonization, junction destabilization and inflammation processes. We will use Neisseria meningitidis as the model of a sepsis causing pathogen as it recapitulates many key features of sepsis pathology and because of recent progress in understanding the mechanisms underlying the disease caused by this bacterium. Identified compounds will then be tested with two other sepsis causing pathogens, Pseudomonas aeruginosa and Staphylococcus aureus. We expect to generate a selection of compounds that can then be developed into drugs to treat deadly bacterial infections.