PqsE is conserved and functionally relevant in Pseudomonas aeruginosa

Abstract

The bacterium Pseudomonas aeruginosa is an opportunistic pathogen responsible for several acute and chronic infections. It produces a diverse array of virulence and survival determinants, many of which are tightly regulated by three interlinked quorum sensing (QS) systems named las, rhl and pqs. RhlR, the transcriptional regulator of the rhl system, activates multiple virulence genes upon binding to its cognate autoinducer signal. Meanwhile, the pqs system relies on 4-hydroxy-2-alkylquinolines (HAQs) as signaling molecules to induce the transcriptional regulator MvfR (PqsR). MvfR then activates the transcription of the pqsABCDE operon, encoding enzymes for HAQ biosynthesis. The final gene in this operon encodes PqsE, a multifunctional protein unique to P. aeruginosa. Beyond its thioesterase activity in HAQ biosynthesis, PqsE stabilizes RhlR, facilitating its regulation of target genes, some of which are implicated in virulence. Because of its role in pathogenicity, PqsE is regarded as a promising therapeutic target for combating P. aeruginosa infections. While the role of PqsE towards the RhlR regulon is increasingly understood in prototypical P. aeruginosa strains such as PA14 and PAO1, its broader relevance as an anti-virulence target remains underexplored. Here, we confirm that PqsE is functionally relevant across a panel of twelve genetically diverse P. aeruginosa strains using metabolite quantification and phenotypic assays. Significant strain-to-strain variations further highlight the importance of studying QS regulation among diverse isolates. Moreover, this study underscores PqsE as a key QS regulator with a conserved role in coordinating virulence determinant production and social behaviors across diverse P. aeruginosa populations. IMPORTANCEPseudomonas aeruginosa is a versatile opportunistic pathogen, naturally tolerant and readily acquiring resistance to multiple antibiotics. Consequently, the World Health Organization identified this bacterium as a high priority pathogen for researching and developing new antimicrobial strategies. P. aeruginosa utilizes quorum sensing, a cell-to-cell communication system, to regulate the expression of several of its virulence factors. Here, we confirm that the PqsE protein is conserved and that its function in quorum sensing, especially towards the RhlR regulator, is maintained across a panel of twelve genetically diverse P. aeruginosa strains. Since PqsE is conserved and unique to this bacterium, it could serve as an ideal target for anti-virulence therapies, offering new alternatives to combat antimicrobial resistance.