Abstract
The human opportunistic pathogen Pseudomonas aeruginosa orchestrates the expression of many genes in a cell density-dependent manner by using quorum sensing (QS). Two acyl-homoserine lactones (AHLs) are involved in QS circuits and contribute to the regulation of virulence factors production, biofilm formation, and antimicrobial sensitivity. Disrupting QS, a strategy referred to as quorum quenching (QQ) can be achieved using exogenous AHL-degrading lactonases. However, the importance of enzyme specificity on quenching efficacy has been poorly investigated. Here, we used two lactonases both targeting the signal molecules N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12 HSL) and butyryl-homoserine lactone (C4 HSL) albeit with different efficacies on C4 HSL. Interestingly, both lactonases similarly decreased AHL concentrations and comparably impacted the expression of AHL-based QS genes. However, strong variations were observed in Pseudomonas Quinolone Signal (PQS) regulation depending on the lactonase used. Both lactonases were also found to decrease virulence factors production and biofilm formation in vitro, albeit with different efficiencies. Unexpectedly, only the lactonase with lower efficacy on C4 HSL was able to inhibit P. aeruginosa pathogenicity in vivo in an amoeba infection model. Similarly, proteomic analysis revealed large variations in protein levels involved in antibiotic resistance, biofilm formation, virulence and diverse cellular mechanisms depending on the chosen lactonase. This global analysis provides evidences that QQ enzyme specificity has a significant impact on the modulation of QS-associated behavior in P. aeruginosa PA14.
Highlights
The human pathogen Pseudomonas aeruginosa is commonly involved in healthcare associated infections and frequently displays drug or multidrug resistance (Sievert et al, 2013; Weiner et al, 2016)
The efficient reduction of C4 HSL observed with SsoPox W263I could originate from a slow but sufficient degradation of this acyl-homoserine lactones (AHLs) throughout the growth of the bacteria leading at the end of the growth to similar results than GcL
We showed that the lactonase GcL, which is highly proficient against both AHLs, exhibited inhibitory activity at concentrations lower than SsoPox W263I for the production of pyocyanin, protease, and elastase
Summary
The human pathogen Pseudomonas aeruginosa is commonly involved in healthcare associated infections and frequently displays drug or multidrug resistance (Sievert et al, 2013; Weiner et al, 2016). This latter constitutes a serious therapeutic threat. In Pseudomonas aeruginosa, three main QS systems have been described namely Las, Rhl, and PQS (i.e., Pseudomonas Quinolone Signal) involving the signal synthases LasI, RhlI, PqsABCDEH, and the receptors LasR, RhlR, and PqsR, respectively (Lee and Zhang, 2015; Papenfort and Bassler, 2016). These systems are interconnected and Las is considered as the global activator of all three systems (Latifi et al, 1996; Déziel et al, 2004)
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