SENBIOTAR: Sensiting Pseudomonas aeruginosa biofilms to antibiotics and reducing virulence through novel target inhibition

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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.