Abstract
Many bacteria use quorum sensing (QS), a bacterial communication system based on the diffusion and perception of small signaling molecules, to synchronize their behavior in a cell-density dependent manner. QS regulates the expression of many genes associated with virulence factor production and biofilm formation. This latter is known to be involved in antibiotic and phage resistance mechanisms. Therefore, disrupting QS, a strategy known as quorum quenching (QQ), appears to be an interesting way to reduce bacterial virulence and increase antibiotic and phage treatment efficiency. In this study, the ability of the QQ enzyme SsoPox-W263I, a lactonase able to degrade acyl-homoserine lactones, was investigated for quenching both virulence and biofilm formation in clinical isolates of Pseudomonas aeruginosa from diabetic foot ulcers, as well as in the PA14 model strain. These strains were further evolved to resist to bacteriophage cocktails. Overall, 10 antibiotics or bacteriophage resistant strains were evaluated and SsoPox-W263I was shown to decrease pyocyanin, protease and elastase production in all strains. Furthermore, a reduction of more than 70% of biofilm formation was achieved in six out of ten strains. This anti-virulence potential was confirmed in vivo using an amoeba infection model, showing enhanced susceptibility toward amoeba of nine out of ten P. aeruginosa isolates upon QQ. This amoeba model was further used to demonstrate the ability of SsoPox-W263I to enhance the susceptibility of sensitive and phage resistant bacteria to bacteriophage and antibiotic.
Highlights
Pseudomonas aeruginosa is an opportunistic human pathogen involved in numerous diseases from otitis to keratitis, wound and burn infections, pneumonia and urinary tract infections (Driscoll et al, 2007)
The antibiotic resistance profiles of the strains revealed that all the clinical isolates presented a significant tolerance to rifampicin, trimethoprim/sulfamethoxazole and nitrofurantoin, confirming previous observations regarding the increasing rate of multi-resistance in diabetic foot infections in the recent years (Lipsky, 2016)
Bacteriophages and quorum quenching (QQ) have emerged as promising therapeutic approaches
Summary
Pseudomonas aeruginosa is an opportunistic human pathogen involved in numerous diseases from otitis to keratitis, wound and burn infections, pneumonia and urinary tract infections (Driscoll et al, 2007). Surveillance of P. aeruginosa infections has revealed trends of increasing resistance to antibiotic treatments (Breidenstein et al, 2011) and the priority to support research and development of effective drugs against antibiotic-resistant P. aeruginosa was recently defined as critical by the World Health Organization (WHO) (Tacconelli et al, 2018) This last decade, bacteriophage (phage) therapy has regained interest as a new weapon to treat antibiotic-resistant infections (Rolain et al, 2015; Domingo-Calap et al, 2016) and is under consideration to treat P. aeruginosa infections. Finding new therapeutic strategies to limit bacterial resistance is of great interest In this way, another alternative to treat P. aeruginosa infections aims to highjack its communication system referred to as quorum sensing (QS). This study shows that QQ is an interesting strategy to treat bacterial infections that can be used to strengthen the effect of antimicrobial treatments
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