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Pseudomonas aeruginosa PumA acts on an endogenous phenazine to promote self-resistance.

ABSTRACT: The activities of critical metabolic and regulatory proteins can be altered by exposure to natural or synthetic redox-cycling compounds. Many bacteria, therefore, possess mechanisms to transport or transform these small molecules. The opportunistic pathogen Pseudomonas aeruginosa PA14 synthesizes phenazines, redox-active antibiotics that are toxic to other organisms but have beneficial effects for their producer. Phenazines activate the redox-sensing transcription factor SoxR and thereby induce the transcription of a small regulon, including the operon mexGHI-opmD, which encodes an efflux pump that transports phenazines, and PA14_35160 (pumA), which encodes a putative monooxygenase. Here, we provide evidence that PumA contributes to phenazine resistance and normal biofilm development, particularly during exposure to or production of strongly oxidizing N-methylated phenazines. We show that phenazine resistance depends on the presence of residues that are conserved in the active sites of other putative and characterized monooxygenases found in the antibiotic producer Streptomyces coelicolor. We also show that during biofilm growth, PumA is required for the conversion of phenazine methosulfate to unique phenazine metabolites. Finally, we compare ?mexGHI-opmD and ?pumA strains in assays for colony biofilm morphogenesis and SoxR activation, and find that these deletions have opposing phenotypic effects. Our results suggest that, while MexGHI-OpmD-mediated efflux has the effect of making the cellular phenazine pool more reducing, PumA acts on cellular phenazines to make the pool more oxidizing. We present a model in which these two SoxR targets function simultaneously to control the biological activity of the P. aeruginosa phenazine pool.

SUBMITTER: Sporer AJ

PROVIDER: S-EPMC6600337 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Pseudomonas aeruginosa PumA acts on an endogenous phenazine to promote self-resistance.

Sporer Abigail J AJ Beierschmitt Christopher C Bendebury Anastasia A Zink Katherine E KE Price-Whelan Alexa A Buzzeo Marisa C MC Sanchez Laura M LM Dietrich Lars E P LEP

Microbiology (Reading, England) 20180409 5

The activities of critical metabolic and regulatory proteins can be altered by exposure to natural or synthetic redox-cycling compounds. Many bacteria, therefore, possess mechanisms to transport or transform these small molecules. The opportunistic pathogen Pseudomonas aeruginosa PA14 synthesizes phenazines, redox-active antibiotics that are toxic to other organisms but have beneficial effects for their producer. Phenazines activate the redox-sensing transcription factor SoxR and thereby induce ...[more]

PMID: 29629858

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Project description:Extracellular electron transfer (EET), the reduction of compounds that shuttle electrons to distal oxidants, can support bacterial survival when preferred oxidants are not directly accessible. EET has been shown to contribute to virulence in some pathogenic organisms and is required for current generation in mediator-based fuel cells. In several species, components of the electron transport chain (ETC) have been implicated in electron shuttle reduction, raising the question of how shuttling-based metabolism is integrated with primary routes of metabolic electron flow. The clinically relevant bacterium Pseudomonas aeruginosa can utilize carbon sources (i.e., electron donors) covering a broad range of reducing potentials and possesses a branched ETC that can be modulated to optimize respiratory efficiency. It also produces electron shuttles called phenazines that facilitate intracellular redox balancing, increasing the complexity of its metabolic potential. In this study, we investigated the reciprocal influence of respiratory metabolism and phenazine-associated physiology in P. aeruginosa PA14. We found that phenazine production affects respiratory activity and terminal oxidase gene expression and that carbon source identity influences the mechanisms enabling phenazine reduction. Furthermore, we found that growth in biofilms, a condition for which phenazine metabolism is critical to normal development and redox balancing, affects the composition of the P. aeruginosa phenazine pool. Together, these findings can aid interpretation of P. aeruginosa behavior during host infection and provide inroads to understanding the cross talk between primary metabolism and shuttling-based physiology in the diverse bacteria that carry out EET.IMPORTANCE The clinically relevant pathogen Pseudomonas aeruginosa uses diverse organic compounds as electron donors and possesses multiple enzymes that transfer electrons from central metabolism to O2 These pathways support a balanced intracellular redox state and produce cellular energy. P. aeruginosa also reduces secondary metabolites called phenazines to promote redox homeostasis and virulence. In this study, we examined the reciprocal relationship between these primary and secondary routes of electron flow. We found that phenazines affect respiratory function and that the complement of phenazines produced is strongly affected by growth in assemblages called biofilms. These results provide a more nuanced understanding of P. aeruginosa redox metabolism and may inform strategies for treating persistent infections caused by this bacterium.

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Pseudomonas aeruginosa PumA acts on an endogenous phenazine to promote self-resistance.

Publications

Pseudomonas aeruginosa PumA acts on an endogenous phenazine to promote self-resistance.

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