Development and validation of a novel screening system for the identification of Pseudomonas aeruginosa virulence inhibitor

The ubiquitous Gram-negative bacterium Pseudomonas aeruginosa is the main agent of lung function decline and mortality in Cystic Fibrosis (CF) patients.Traditional antimicrobial approaches targeting the bacterial viability and growth have proven to be unsuccessful in the treatment of chronic P. aeruginosa infection because of the emergence of resistance. A novel and promising approach is screening for molecules that inhibit the traits that are specifically required for P. aeruginosa virulence.Bacteria live in communities within the infected human host, and their group-behaviour has a deep influence on the expression of virulence traits. The quorum sensing and pyoverdine signalling regulatory systems control the group-behaviour of P. aeruginosa and the expression of virulence factors, biofilm formation and antibiotic resistance, ultimately enhancing the fitness of P. aeruginosa in the host environment.The underlying rationale of this project is the identification of a new generation of drugs acting against the quorum sensing and pyoverdine signalling systems, and hence against the P. aeruginosa ability to cause infection. The use of these novel drugs would provide the host immune system with a better chance of clearing the infection, and could circumvent the problem of the emergence of drug-resistant strains.The specific goal of the project is to set-up, validate and use novel high-throughput screening systems to detect molecules suppressing P. aeruginosa quorum sensing and pyoverdine signalling. The screening systems developed in this project will be used to screen libraries of synthetic and natural compounds. Moreover, these systems will provide the research community with a valuable tool for the discovery of new anti-P. aeruginosa compounds.