New Pqs Quorum Sensing System Inhibitor as an Antibacterial Synergist against Multidrug-Resistant Pseudomonas aeruginosa .

Development of new bacterial biofilm inhibitors as antibacterial synergists is an effective strategy to solve the resistance of Pseudomonas aeruginosa . In this paper, a series of 3-hydroxy-pyridin-4(1 H )-ones were synthesized and evaluated, and the hit compound ( 20p ) was identified with the effects of inhibiting the production of pyocyanin (IC 50 = 8.6 μM) and biofilm formation (IC 50 = 4.5 μM). Mechanistic studies confirmed that 20p inhibits the formation of bacterial biofilm by inhibiting the expression of pqsA , blocking pqs quorum sensing system quinolone biosynthesis. Moreover, we systematically investigated the bactericidal effects of combining currently approved antibiotics for CF including tobramycin, ciprofloxacin, and colistin E with 20p , which showed obvious antibacterial synergy to overcome antibiotics resistance in multidrug-resistant P. aeruginosa biofilms. The result indicates that compound 20p may be used in the future as a potentially novel antibacterial synergist candidate for the treatment of P. aeruginosa infections.