Dataset Information

Rule-based regulatory and metabolic model for Quorum sensing in P. aeruginosa.

ABSTRACT:

Background

In the pathogen P. aeruginosa, the formation of virulence factors is regulated via Quorum sensing signaling pathways. Due to the increasing number of strains that are resistant to antibiotics, there is a high interest to develop novel antiinfectives. In the combat of resistant bacteria, selective blockade of the bacterial cell-to-cell communication (Quorum sensing) has gained special interest as anti-virulence strategy. Here, we modeled the las, rhl, and pqs Quorum sensing systems by a multi-level logical approach to analyze how enzyme inhibitors and receptor antagonists effect the formation of autoinducers and virulence factors.

Results

Our rule-based simulations fulfill the behavior expected from literature considering the external level of autoinducers. In the presence of PqsBCD inhibitors, the external HHQ and PQS levels are indeed clearly reduced. The magnitude of this effect strongly depends on the inhibition level. However, it seems that the pyocyanin pathway is incomplete.

Conclusions

To match experimental observations we suggest a modified network topology in which PqsE and PqsR acts as receptors and an autoinducer as ligand that up-regulate pyocyanin in a concerted manner. While the PQS biosynthesis is more appropriate as target to inhibit the HHQ and PQS formation, blocking the receptor PqsR that regulates the biosynthesis reduces the pyocyanin level stronger.

SUBMITTER: Schaadt NS

PROVIDER: S-EPMC3765737 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Publications

Rule-based regulatory and metabolic model for Quorum sensing in P. aeruginosa.

Schaadt Nadine S NS Steinbach Anke A Hartmann Rolf W RW Helms Volkhard V

BMC systems biology 20130821

<h4>Background</h4>In the pathogen P. aeruginosa, the formation of virulence factors is regulated via Quorum sensing signaling pathways. Due to the increasing number of strains that are resistant to antibiotics, there is a high interest to develop novel antiinfectives. In the combat of resistant bacteria, selective blockade of the bacterial cell-to-cell communication (Quorum sensing) has gained special interest as anti-virulence strategy. Here, we modeled the las, rhl, and pqs Quorum sensing sys ...[more]

PMID: 23965312

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Project description:UnlabelledPseudomonas aeruginosa uses N-acyl-homoserine lactone (AHL)-dependent quorum sensing (QS) systems to control the expression of secreted effectors. These effectors can be crucial to the ecological fitness of the bacterium, playing roles in nutrient acquisition, microbial competition, and virulence. In this study, we investigated the metabolic consequences of AHL-dependent QS by monitoring the metabolic profile(s) of a lasI rhlI double mutant (unable to make QS signaling molecules) and its wild-type progenitor as they progressed through the growth curve. Analysis of culture supernatants by (1)H-nuclear magnetic resonance ((1)H-NMR) spectroscopy revealed that at the point where AHL concentrations peaked in the wild type, the metabolic footprints (i.e., extracellular metabolites) of the wild-type and lasI rhlI mutant diverged. Subsequent gas chromatography-mass spectrometry (GC-MS)-based analysis of the intracellular metabolome revealed QS-dependent perturbations in around one-third of all identified metabolites, including altered concentrations of tricarboxylic acid (TCA) cycle intermediates, amino acids, and fatty acids. Further targeted fatty acid methyl ester (FAME) GC-MS-based profiling of the cellular total fatty acid pools revealed that QS leads to changes associated with decreased membrane fluidity and higher chemical stability. However, not all of the changes we observed were necessarily a direct consequence of QS; liquid chromatography (LC)-MS analyses revealed that polyamine levels were elevated in the lasI rhlI mutant, perhaps a response to the absence of QS-dependent adaptations. Our data suggest that QS leads to a global readjustment in central metabolism and provide new insight into the metabolic changes associated with QS during stationary-phase adaptation.ImportanceQuorum sensing (QS) is a transcriptional regulatory mechanism that allows bacteria to coordinate their gene expression profile with the population cell density. The opportunistic human pathogen Pseudomonas aeruginosa uses QS to control the production of secreted virulence factors. In this study, we show that QS elicits a global "metabolic rewiring" in P. aeruginosa. This metabolic rerouting of fluxes is consistent with a variety of drivers, ranging from altered QS-dependent transcription of "metabolic genes" through to the effect(s) of global "metabolic readjustment" as a consequence of QS-dependent exoproduct synthesis, as well as a general stress response, among others. To our knowledge, this is the first study of its kind to assess the global impact of QS on the metabolome.

Project description:UnlabelledMany species of bacteria use a cell-cell communication system called quorum sensing (QS) to coordinate group activities. QS systems frequently regulate the production of exoproducts. Some of these products, such as proteases, are "public goods" that are shared among the population and vulnerable to cheating by nonproducing members of the population. Because the QS system of the opportunistic pathogen Pseudomonas aeruginosa regulates several public goods, it can serve as a model for studying cooperation. Bacteria also commonly regulate antimicrobial production through QS. In this study, we focused on the hypothesis that QS-regulated antimicrobials may be important for P. aeruginosa to protect against cheating by another bacterial species, Burkholderia multivorans. We assessed laboratory cocultures of P. aeruginosa and B. multivorans and investigated the importance of three P. aeruginosa QS-regulated antimicrobials, hydrogen cyanide, rhamnolipids, and phenazines, for competition. We found that P. aeruginosa dominates cocultures with B. multivorans and that the three antimicrobials together promote P. aeruginosa competitiveness, with hydrogen cyanide contributing the greatest effect. We show that these QS-regulated antimicrobials are also critical for P. aeruginosa to prevent B. multivorans from cheating under nutrient conditions where both species require a P. aeruginosa quorum-regulated protease for growth. Together our results highlight the importance of antimicrobials in protecting cooperating populations from exploitation by other species that can act as cheaters.ImportanceCooperative behaviors are threatened by social cheating, wherein individuals do not produce but nonetheless benefit from shared public goods. Bacteria have been shown to use several genetic mechanisms to restrain the emergence of cheaters from within the population, but public goods might also be used by other bacterial species in the vicinity. We demonstrate that a public good produced by Pseudomonas aeruginosa can be used by another species, Burkholderia multivorans, to obtain carbon and energy. We also show that P. aeruginosa antimicrobials that are coregulated with the public good prevent invasion by the cheating species. Our results demonstrate that cross-species cheating can occur and that coregulation of public goods with antimicrobials may stabilize cooperative behavior in mixed microbial communities.

Dataset Information

Rule-based regulatory and metabolic model for Quorum sensing in P. aeruginosa.

Background

Results

Conclusions

Publications

Rule-based regulatory and metabolic model for Quorum sensing in P. aeruginosa.

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