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The chronic lung infection caused by  Pseudomonas aeruginosa  is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. Antivirulence drugs targeting  P. aeruginosa  quorum sensing (QS) systems are intensively studied as antibiotics substitutes or adjuvants. Previous studies, carried out in non-CF  P. aeruginosa  reference strains, showed that the old drugs niclosamide and clofoctol could be successfully repurposed as antivirulence drugs targeting the  las  and  pqs  QS systems, respectively. However, frequent emergence of QS-defective mutants in the CF lung undermines the use of QS inhibitors in CF therapy. Here, QS signal production and susceptibility to niclosamide and clofoctol have been investigated in 100  P. aeruginosa  CF isolates, with the aim of broadening current knowledge on the potential of anti-QS compounds in CF therapy. Results showed that 85, 78, and 69% of the CF isolates from our collection were proficient for the  pqs ,  rhl , and  las  QS systems, respectively. The ability of both niclosamide and clofoctol to inhibit QS and virulence  in vitro  was highly variable and strain-dependent. Niclosamide showed an overall low range of activity and its negative effect on  las  signal production did not correlate with a decreased production of virulence factors. On the other hand, clofoctol displayed a broader QS inhibitory effect in CF isolates, with consequent reduction of the  pqs -controlled virulence factor pyocyanin. Overall, this study highlights the importance of testing new antivirulence drugs against large panels of  P. aeruginosa  CF clinical isolates before proceeding to further pre-clinical studies and corroborates previous evidence that strains naturally resistant to QS inhibitors occur among CF isolates. However, it is also shown that resistance to  pqs  inhibitors is less frequent than resistance to  las  inhibitors, thus supporting the development of  pqs  inhibitors for antivirulence therapy in CF.

In vitro Activity of Antivirulence Drugs Targeting the las or pqs Quorum Sensing Against Cystic Fibrosis Pseudomonas aeruginosa Isolates