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

Abstract

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.

PqsE Expands and Differentially Modulates the RhlR Quorum Sensing Regulon in Pseudomonas aeruginosa

“…In accordance, both the RhlR inhibitor meta-bromo-thiolactone and the PqsE inhibitors nitrofurazone and erythromycin estolate downregulate PqsE/RhlR-dependent virulence traits in P. aeruginosa , including pyocyanin production and biofilm formation ( 84 , 85 ). While some rewiring of the canonical QS regulatory cascade has been observed in P. aeruginosa clinical isolates ( 86 – 88 ), strains defective in the rhl or pqs systems are less frequently isolated from cystic fibrosis patients compared to las- deficient strains ( 89 – 91 ). Overall, these observations support PqsE and RhlR as promising targets for the development of antivirulence drugs reducing the pathogenic potential of P. aeruginosa .…”

Cross-Species Protection to Innate Immunity Mediated by A Bacterial Pigment

“…As the distance between the two colonies further increased, HQNO concentration was likely too low to induce STX production (yellow arrows). In addition, different P. aeruginosa laboratory and clinical strains can produce varying amounts of HQNO, ranging from 0 to 50μM 32,33 . Mucoid P. aeruginosa , with an overproduction of alginate, is commonly isolated from chronic infections and can co-exist with S. aureus better than the non-mucoid counterparts 35 .…”

“…Additionally, P. aeruginosa clinical isolates synthesize varying levels of HQNO 32,33 . We screened 29 P. aeruginosa clinical isolates, derived from CF lung and wound infections (Table S1), to examine their ability to induce STX production in USA300.…”

Synergistic Activity of Colistin in Combination with Clofoctol against Colistin Resistant Gram-Negative Pathogens

“…On these bases, clofoctol has been proposed for the treatment of different obstructive lung diseases, including asthma, lung cancer, and SARS-CoV-2 infection ( 8 ). Clofoctol also inhibits the quorum sensing (QS) cell-cell communication system of Pseudomonas aeruginosa , causing virulence attenuation ( 9 , 10 ). Interestingly, a colistin-adjuvant activity has recently been discovered in two inhibitors of the P. aeruginosa QS, i.e., niclosamide and furanone C-30 ( 11 , 12 ), raising the question of whether clofoctol could also display this activity.…”