Sensiting Pseudomonas aeruginosa biofilms to antibiotic and reducing virulencce through novel target inhibition

The traditional approach to combating bacterial infections has been based on the use of antibiotics which kill bacteria or inhibit their growth. There has also been a strong emphasis on the identification of essential gene targets for drug intervention. A major problem with therapeutic approaches targeting viability is that they induce strong selective pressures resulting in the rapid emergence of antimicrobial resistance. An alternate approach is to inhibit virulence rather than bacterial viability and this will be explored in the SENBIOTAR project. In the opportunistic human pathogen Pseudomonas aeruginosa, virulence is co-ordinately controlled at the bacterial population level through quorum sensing (QS), a global cell-to-cell communication system employing diffusible signal molecules. P. aeruginosa strains with mutations in the Pseudomonas Quinolone Signal (PQS) QS pathway are avirulent in experimental animal infections. The partners of this consortium will exploit this information by optimising hit compounds and peptide nucleic acids (PNAs) they identified previously which target PQS biosynthesis and/or PQS signal transduction. These hits have been shown to not only render P. aeruginosa avirulent but also to sensitize biofilms to the action of antibiotics. One of the limitations of using inhibitors of virulence is the fact that immunocompromised patients may not be able to clear the targeted pathogen efficiently. However, if the pathogen can, at the same time, be sensitised to antibiotics then there is great scope for dual therapy with PQS inhibitors and antibiotics. SENBIOTAR will bring together world experts in QS, medicinal chemistry, PNAs, drug delivery and preclinical studies to optimise the activity of the hit compounds and PNAs (hit-to-lead optimization) with the intention of identifying lead compounds which strongly inhibit QS, attenuate virulence and sensitise biofilms to conventional antibiotics at sub-micromolar concentrations. This will be achieved by improving (a) their physicochemical properties without the emergence of cytotoxicity, and (b) delivery to the site of infection. These studies will be performed using a combination of in vitro virulence and biofilm bioassays alongside experimental animal lung infection models. The lead compounds developed by SENBIOTAR will also have significant potential for the treatment of wound, bloodstream and medical-device associated infections caused by P. aeruginosa.