<i>Pseudomonas aeruginosa</i>
            Pyocyanin Is Critical for Lung Infection in Mice

Lau, Gee W.; Ran, Huimin; Kong, Fanrong; Hassett, Daniel J.; Mavrodi, Dmitri V.

doi:10.1128/iai.72.7.4275-4278.2004

Cited by 340 publications

(311 citation statements)

References 20 publications

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“…The opportunistic pathogen P. aeruginosa produces phenazines, antibiotics that contribute to virulence not only by directly damaging host tissues but also by enhancing pseudomonad fitness during host colonization (18,21,22,46,55). In particular, P. aeruginosa is well known for production of the bright blue phenazine pyocyanin, which contributes to the coloration of sputum and pus associated with infections.…”

Section: Discussionmentioning

confidence: 99%

“…P. aeruginosa is an opportunistic pathogen that causes biofilmbased infections with devastating effects (16). This Gram-negative bacterium synthesizes phenazines, redox-cycling antibiotics that affect redox homeostasis and gene expression in both the producer and hosts (17)(18)(19)(20)(21)(22). Several years ago, our group showed that pyocyanin (5-N-methyl-1-hydroxyphenazine), the most wellknown P. aeruginosa phenazine (23), activates the redox-active transcription factor SoxR and thereby induces expression of a small regulon that includes the RND (resistance-nodulation-division) efflux pump-encoding operon mexGHI-opmD (hereafter referred to as "mex") (24,25).…”

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confidence: 99%

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The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Sakhtah

Koyama

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

159

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Redox-cycling compounds, including endogenously produced phenazine antibiotics, induce expression of the efflux pump MexGHIOpmD in the opportunistic pathogen Pseudomonas aeruginosa. Previous studies of P. aeruginosa virulence, physiology, and biofilm development have focused on the blue phenazine pyocyanin and the yellow phenazine-1-carboxylic acid (PCA). In P. aeruginosa phenazine biosynthesis, conversion of PCA to pyocyanin is presumed to proceed through the intermediate 5-methylphenazine-1-carboxylate (5-Me-PCA), a reactive compound that has eluded detection in most laboratory samples. Here, we apply electrochemical methods to directly detect 5-Me-PCA and find that it is transported by MexGHIOpmD in P. aeruginosa strain PA14 planktonic and biofilm cells. We also show that 5-Me-PCA is sufficient to fully induce MexGHI-OpmD expression and that it is required for wild-type colony biofilm morphogenesis. These physiological effects are consistent with the high redox potential of 5-Me-PCA, which distinguishes it from other well-studied P. aeruginosa phenazines. Our observations highlight the importance of this compound, which was previously overlooked due to the challenges associated with its detection, in the context of P. aeruginosa gene expression and multicellular behavior. This study constitutes a unique demonstration of efflux-based selfresistance, controlled by a simple circuit, in a Gram-negative pathogen.phenazine | RND efflux | MexGHI-OpmD | biofilm | antibiotic

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Sakhtah

Koyama

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

159

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“…The bacterium secretes a large number of products that contribute to virulence. These include type III-secreted exotoxins that disrupt the cytoskeleton and lyse the cells, as well as proteases, phospholipase, rhamnolipids, and hemolysin (3)(4)(5)(6)(7)(8). In addition, P. aeruginosa produce and secrete the blue pigment pyocyanin (PYO), which is found in the sputum of patients with CF and bronchiectasis at concentrations up to 100 M; this is responsible for the blue-green color often observed in CF sputum (4,5,9,10).…”

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confidence: 99%

Redox-independent Activation of NF-κB by Pseudomonas aeruginosa Pyocyanin in a Cystic Fibrosis Airway Epithelial Cell Line

Schwarzer

Fischer³

et al. 2008

Journal of Biological Chemistry

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The roles of the Pseudomonas aeruginosa-derived pigment pyocyanin (PYO) as an oxidant and activator of the proinflammatory transcription factor NF-B were tested in a cystic fibrosis (CF) airway epithelial cell line, CF15. 100 M PYO on its own had no effect or only small effects to activate NF-B (<1.5-fold), but PYO synergized with the TLR5 agonist flagellin. Flagellin activated NF-B 4 -20-fold, and PYO increased these activations >2. Pseudomonas aeruginosa is commonly present in lungs of cystic fibrosis (CF) 2 and immunocompromised patients (1, 2). The bacterium secretes a large number of products that contribute to virulence. These include type III-secreted exotoxins that disrupt the cytoskeleton and lyse the cells, as well as proteases, phospholipase, rhamnolipids, and hemolysin (3-8). In addition, P. aeruginosa produce and secrete the blue pigment pyocyanin (PYO), which is found in the sputum of patients with CF and bronchiectasis at concentrations up to 100 M; this is responsible for the blue-green color often observed in CF sputum (4, 5, 9, 10). PYO-deficient P. aeruginosa elicits less mortality in P. aeruginosa-mediated burn-sepsis model in mice, and PYO appears to be important for persistence of P. aeruginosa in lungs of CF patients (3, 4, 11). PYO has a multitude of effects on the physiology of epithelial cells, including inhibition or alteration of antioxidant enzymes (12, 13), ciliary function (14), cellular metabolism, and organelle H ϩ v-ATPase (2, 15). A key aspect of PYO pathology may result from its ability to trigger inflammation leading to the influx of neutrophils to the P. aeruginosa-infected region; PYO stimulates ICAM-1 and IL8 production on its own and also synergizes with IL1␤ and TNF␣ in stimulating IL8 production (16 -18). The resulting IL8 production triggers polymorphonuclear leukocyte infiltration. The polymorphonuclear leukocytes are critical for fighting infections through production of reactive oxygen species (ROS) and proteases, but these products also contribute to the tissue destruction characteristic of CF.PYO activation of IL8 production may occur through effects on cellular signaling leading to activation of the transcription factors AP-1, NF-IL6/C-EBP, and/or NF-B, which control IL8 production (19). It is widely assumed that the effects of PYO on signaling are mediated at least in part through its ability to redox cycle with cellular NADPH and/or GSH leading to the production of ROS (9,13,20,21) and oxidation of the cytosol and/or mitochondria (21,22). Experiments using the electron spin resonance method showed that PYO caused the production of superoxide (O 2 . ) but not hydroxyl radical (HO ⅐ ), indicating that O 2 . and, through the action of superoxide dismutase, H 2 O 2 might contribute to proinflammatory signaling by PYO (16). In addition, the antioxidant N-acetylcysteine and the HO ⅐ scavenger DMSO reduced the proinflammatory effects of PYO, consistent with PYO triggering inflammatory processes through its pro-oxidant effects (18). However, none of these experiment...

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“…Structurally simple phenazines such a phenazine-1-carboxylic acid (PCA) and its hydroxy and carboxamide derivatives are produced by beneficial strains of Pseudomonas on the roots of plants, where they have a critical role in suppressing fungal pathogens (2,3) and can contribute to the ecological competence of the strains that produce them (4). The antibiotic properties of pyocyanin, the blue phenazine synthesized in human tissues by the opportunistic pathogen Pseudomonas aeruginosa, were first reported in the late 1890s, although interest now focuses on its role as a virulence determinant in chronic and acute lung disease (5,6). The antibiotic, antiparasitic, and antitumor activities of naturally occurring phenazine compounds also have stimulated interest in the development of synthetic analogues tailored to particular therapeutic applications, but progress has been limited by the lack of efficient and generally applicable methods for the synthesis of substituted phenazines (1).…”

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confidence: 99%

Structure and function of the phenazine biosynthetic protein PhzF from Pseudomonas fluorescens

Blankenfeldt

Kuzin

Skarina

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

124

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Phenazines produced by Pseudomonas and Streptomyces spp. are heterocyclic nitrogen-containing metabolites with antibiotic, antitumor, and antiparasitic activity. The antibiotic properties of pyocyanin, produced by Pseudomonas aeruginosa, were recognized in the 1890s, although this blue phenazine is now known to be a virulence factor in human disease. Despite their biological significance, the biosynthesis of phenazines is not fully understood. Here we present structural and functional studies of PhzF, an enzyme essential for phenazine synthesis in Pseudomonas spp. PhzF shares topology with diaminopimelate epimerase DapF but lacks the same catalytic residues. The structure of PhzF in complex with its substrate, trans-2,3-dihydro-3-hydroxyanthranilic acid, suggests that it is an isomerase using the conserved glutamate E45 to abstract a proton from C3 of the substrate. The proton is returned to C1 of the substrate after rearrangement of the double-bond system, yielding an enol that converts to the corresponding ketone. PhzF is a dimer that may be bifunctional, providing a shielded cavity for ketone dimerization via double Schiff-base formation to produce the phenazine scaffold. Our proposed mechanism is supported by mass and NMR spectroscopy. The results are discussed in the context of related structures and protein sequences of unknown biochemical function.active site residues ͉ catalytic activity ͉ x-ray structure

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Pseudomonas aeruginosa Pyocyanin Is Critical for Lung Infection in Mice

Cited by 340 publications

References 20 publications

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

The Pseudomonas aeruginosa efflux pump MexGHI-OpmD transports a natural phenazine that controls gene expression and biofilm development

Redox-independent Activation of NF-κB by Pseudomonas aeruginosa Pyocyanin in a Cystic Fibrosis Airway Epithelial Cell Line

Structure and function of the phenazine biosynthetic protein PhzF from Pseudomonas fluorescens

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