Abstract
Pseudomonas aeruginosa is the predominant pathogen in pulmonary infections associated with cystic fibrosis. Quorum sensing (QS) systems regulate the production of virulence factors and play an important role in the establishment of successful P. aeruginosa infections. Inhibition of the QS system (termed quorum quenching) renders the bacteria avirulent thus serving as an alternative approach in the development of novel antibiotics. Quorum quenching in Gram negative bacteria can be achieved by preventing the accumulation of N-acyl homoserine lactone (AHL) signaling molecule via enzymatic degradation. Previous work by us has shown that PvdQ acylase hydrolyzes AHL signaling molecules irreversibly, thereby inhibiting QS in P. aeruginosa in vitro and in a Caenorhabditis elegans model of P. aeruginosa infection. The aim of the present study is to assess the therapeutic efficacy of intranasally instilled PvdQ acylase in a mouse model of pulmonary P. aeruginosa infection. First, we evaluated the deposition pattern of intranasally administered fluorochrome-tagged PvdQ (PvdQ-VT) in mice at different stages of pulmonary infection by in vivo imaging studies. Following intranasal instillation, PvdQ-VT could be traced in all lung lobes with 42 ± 7.5% of the delivered dose being deposited at 0 h post-bacterial-infection, and 34 ± 5.2% at 72 h post bacterial-infection. We then treated mice with PvdQ during lethal P. aeruginosa pulmonary infection and that resulted in a 5-fold reduction of lung bacterial load and a prolonged survival of the infected animals with the median survival time of 57 hin comparison to 42 h for the PBS-treated group. In a sublethal P. aeruginosa pulmonary infection, PvdQ treatment resulted in less lung inflammation as well as decrease of CXCL2 and TNF-α levels at 24 h post-bacterial-infection by 15 and 20%, respectively. In conclusion, our study has shown therapeutic efficacy of PvdQ acylase as a quorum quenching agent during P. aeruginosa infection.
Highlights
Pseudomonas aeruginosa is an opportunistic Gram negative bacterium that is mainly associated with hospital-acquired infections and known as the major pathogen in cystic fibrosis (CF) patients (Driscoll et al, 2007)
Purified PvdQ Is Active and Quenches the Virulence of P. aeruginosa Biosensors in a Dose-Dependent Manner PvdQ was purified with a yield of 30 mg L−1 of cell culture
Effectivity of PvdQ in attenuating virulence of P. aeruginosa was monitored by employing biosensors with a chromosomal integration of a luciferase gene controlled by the Quorum sensing (QS)-regulated lasB promoter or rhlA promoter
Summary
Pseudomonas aeruginosa is an opportunistic Gram negative bacterium that is mainly associated with hospital-acquired infections and known as the major pathogen in cystic fibrosis (CF) patients (Driscoll et al, 2007). Deletion of either the AHL synthases or AHL receptors resulted in a downregulation of QS-regulated virulence factors, such as rhamnolipids, elastase protease, pyocyanin siderophore, and biofilm formation (Passador et al, 1993; Whiteley et al, 1999). These QS mutants are less pathogenic in animal models in comparison to the wild-type (Wu et al, 2001; Imamura et al, 2005), revealing the importance of this system for establishing successful infections. These findings opened up a possibility of attacking QS system as a new antivirulence drug therapy
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