Understanding the Mechanistic Link Between the Twin-Arginine Transport (Tat) System and Quorum Sensing in Pseudomonas aeruginosa in order to Design and Develop Novel Antivirulence/Adjuvant Drugs (360G-Wellcome-204009_Z_17_A)

Pseudomonas aeruginosa is a common human pathogen that causes serious infections and is intrinsically resistant to many antibiotics. P. aeruginosa has multiple interlinked chemical messaging (quorum sensing) systems which control production of virulence factors, synchronisation of bacteria and formation of multidrug-resistant biofilms that lead to immune evasion and establishment of disease. One such system is 2-alkyl-4-quinolone (AQ) signalling and inactivation of this results in bacteria unable to cause infection. Perturbation of AQ signalling would therefore be an ideal target for new antimicrobial compounds. Inhibition of the Twin-arginine transport (Tat) system, the only pathway that secretes fully folded proteins in P. aeruginosa, perturbs AQ signalling yet the precise mechanism is not known. To identify which substrates of the Tat system influence AQs, a bioluminescent gene expression reporter that responds to AQs will be monitored in Tat substrate mutants, and AQs will be localised within bacteria. Novel Tat inhibitors will also be optimised and tested for antimicrobial potential. The aim is to understand the Tat-AQ signalling link alongside discovering and developing new antibiotics that target the Tat system, and therefore, virulence. Virulence is not an essential biological process, so antibiotic-resistance is less likely to develop due to a lower selective pressure.