Chemical Genetics Reveals Environment-Specific Roles for Quorum Sensing Circuits in Pseudomonas aeruginosa

Nutritional cues differentially influence the activities of the three quorum sensing (QS) circuits—Las, Rhl, and Pqs—in the pathogen Pseudomonas aeruginosa. A full understanding of how these systems work together to tune virulence factor production to the environment is lacking. Here, we used chemical probes to evaluate the contribution of each QS circuit to virulence in wild-type P. aeruginosa under defined environmental conditions. Our results indicate that Rhl and Pqs drive virulence factor production in phosphate- and iron-limiting environments, while Las has a minor influence. Consequently, simultaneous inhibition of Rhl and Pqs can attenuate virulence in environments where Las inhibition fails. The activity trends generated in this study can be extrapolated to predict QS inhibitor activity in infection-relevant environments, such as cystic fibrosis sputum. These results indicate that environmental signals can drastically alter the efficacy of small-molecule QS inhibitors in P. aeruginosa and possibly other pathogens. [Display omitted] •The Rhl and Pqs QS systems tune virulence factor production to the environment•Small-molecule QS inhibitors have environment-dependent activity•Cocktails of QS inhibitors can best attenuate virulence factor production•Inhibitor cocktails are active in environments that mimic infection (CF sputum) Welsh and Blackwell show that small-molecule quorum sensing (QS) inhibitors have environment-dependent activity and that cocktails of QS inhibitors can attenuate virulence factor production under conditions where targeting a single QS circuit is ineffective.