Abstract
The opportunistic pathogen Pseudomonas aeruginosa employs quorum sensing to govern the production of many virulence factors. Interference with quorum sensing signaling has therefore been put forward as an attractive approach to disarm this pathogen. Here, we analyzed the quorum quenching properties of natural and engineered (2-alkyl-)3-hydroxy-4(1H)-quinolone 2,4-dioxygenases (HQDs) that inactivate the P. aeruginosa signal molecule PQS (Pseudomonas quinolone signal; 2-heptyl-3-hydroxy-4(1H)-quinolone). When added exogenously to P. aeruginosa cultures, all HQDs tested significantly reduced the levels of PQS and other alkylquinolone-type secondary metabolites deriving from the biosynthetic pathway, such as the respiratory inhibitor 2-heptyl-4-hydroxyquinoline N-oxide. HQDs from Nocardia farcinica and Streptomyces bingchenggensis, which combine low KM values for PQS with thermal stability and resilience in the presence of P. aeruginosa exoproducts, respectively, attenuated production of the virulence factors pyocyanin and pyoverdine. A delay in mortality was observed when Galleria mellonella larvae were infected with P. aeruginosa suspensions treated with the S. bingchenggensis HQD or with inhibitors of alkylquinolone biosynthesis. Our data indicate that quenching of PQS signaling has potential as an anti-virulence strategy; however, an efficient anti-virulence therapy against P. aeruginosa likely requires a combination of agents addressing multiple targets.
Highlights
Pseudomonas aeruginosa is a ubiquitous environmental bacterium and opportunistic pathogen associated with a wide range of nosocomial infections
Many virulence-associated behaviors are regulated via quorum sensing (QS), a cell-to-cell communication mechanism employed by bacteria to sense and collectively respond to cell density and environmental cues
Assays to determine quenching of virulence factor production by PQS dioxygenases were performed with P. aeruginosa strains PAO1 (Nottingham strain, Holloway collection) and
Summary
Pseudomonas aeruginosa is a ubiquitous environmental bacterium and opportunistic pathogen associated with a wide range of nosocomial infections. It typically affects immunocompromised and hospitalized individuals and is a major pathogen associated with pulmonary infections, in patients with cystic fibrosis (CF) [1,2]. Infections caused by P. aeruginosa are increasingly difficult to treat due to intrinsic and acquired antibiotic resistances and the spread of antibiotic-resistant strains [3]. Key factors contributing to the pathogenesis of P. aeruginosa include the production of a plethora of virulence factors, the formation of biofilms, and its metabolic versatility and high adaptability [1].
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