scholarly journals Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

2018 ◽  
Vol 14 ◽  
pp. 2627-2645 ◽  
Author(s):  
Christian Schütz ◽  
Martin Empting
Keyword(s):  
Quorum Sensing ◽  
Drug Targets ◽  
Opportunistic Pathogen ◽  
Infection Process ◽  
Signal Molecules ◽  
Binding Modes ◽  
Pseudomonas Quinolone Signal ◽  
Signalling Network ◽  
Wide Group ◽  
The Individual

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa causes severe nosocomial infections. It uses quorum sensing (QS) to regulate and coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and highlights the published drug discovery efforts providing insights into the compound binding modes if available. Furthermore, suitability of the individual targets for pathoblocker design is discussed.

scholarly journals Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

2019 ◽  
Vol 85 (24) ◽  
Author(s):  
Tasia Joy Lightly ◽  
Kara L. Frejuk ◽  
Marie-Christine Groleau ◽  
Laurent R. Chiarelli ◽  
Cor Ras ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Phenylacetic Acid ◽  
Coenzyme A ◽  
Opportunistic Pathogen ◽  
Burkholderia Cenocepacia ◽  
Signal Molecules ◽  
Wild Type ◽  
Content Type ◽  
Opportunistic Bacteria ◽  
Virulent Phenotype

ABSTRACT During phenylalanine catabolism, phenylacetic acid (PAA) is converted to phenylacetyl coenzyme A (PAA-CoA) by a ligase, PaaK, and then PAA-CoA is epoxidized by a multicomponent monooxygenase, PaaABCDE, before further degradation through the tricarboxylic acid (TCA) cycle. In the opportunistic pathogen Burkholderia cenocepacia, loss of paaABCDE attenuates virulence factor expression, which is under the control of the LuxIR-like quorum sensing (QS) system, CepIR. To further investigate the link between CepIR-regulated virulence and PAA catabolism, we created knockout mutants of the first step of the pathway (PAA-CoA synthesis by PaaK) and characterized them in comparison to a paaABCDE mutant using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and virulence assays. We found that while loss of PaaABCDE decreased virulence, deletion of the paaK genes resulted in a more virulent phenotype than that of the wild-type strain. Deletion of either paaK or paaABCDE led to higher levels of released PAA but no differences in levels of internal accumulation compared to the wild-type level. While we found no evidence of direct cepIR downregulation by PAA-CoA or PAA, a low-virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. On the other hand, removal of paaABCDE in the cepR mutant did not impact its attenuated phenotype. Together, our results suggest an indirect role for PAA-CoA in suppressing B. cenocepacia CepIR-activated virulence. IMPORTANCE The opportunistic pathogen Burkholderia cenocepacia uses a chemical signal process called quorum sensing (QS) to produce virulence factors. In B. cenocepacia, QS relies on the presence of the transcriptional regulator CepR which, upon binding QS signal molecules, activates virulence. In this work, we found that even in the absence of CepR, B. cenocepacia can elicit a pathogenic response if phenylacetyl-CoA, an intermediate of the phenylacetic acid degradation pathway, is not produced. Instead, accumulation of phenylacetyl-CoA appears to attenuate pathogenicity. Therefore, we have discovered that it is possible to trigger virulence in the absence of CepR, challenging the classical view of activation of virulence by this QS mechanism. Our work provides new insight into the relationship between metabolism and virulence in opportunistic bacteria. We propose that in the event that QS signaling molecules cannot accumulate to trigger a pathogenic response, a metabolic signal can still activate virulence in B. cenocepacia.

scholarly journals PqsE Functions Independently of PqsR-Pseudomonas Quinolone Signal and Enhances the rhl Quorum-Sensing System

2008 ◽  
Vol 190 (21) ◽  
pp. 7043-7051 ◽  
Author(s):  
John M. Farrow ◽  
Zoe M. Sund ◽  
Matthew L. Ellison ◽  
Dana S. Wade ◽  
James P. Coleman ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Virulence Factors ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Chronic Infections ◽  
Signaling Systems ◽  
Sensing System ◽  
Pseudomonas Quinolone Signal ◽  
Quorum Sensing System ◽  
Hostile Environments

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that causes both acute and chronic infections in immunocompromised individuals. This gram-negative bacterium produces a battery of virulence factors that allow it to infect and survive in many different hostile environments. The control of many of these virulence factors falls under the influence of one of three P. aeruginosa cell-to-cell signaling systems. The focus of this study, the quinolone signaling system, functions through the Pseudomonas quinolone signal (PQS), previously identified as 2-heptyl-3-hydroxy-4-quinolone. This signal binds to and activates the LysR-type transcriptional regulator PqsR (also known as MvfR), which in turn induces the expression of the pqsABCDE operon. The first four genes of this operon are required for PQS synthesis, but the fifth gene, pqsE, is not. The function of the pqsE gene is not known, but it is required for the production of multiple PQS-controlled virulence factors and for virulence in multiple models of infection. In this report, we show that PqsE can activate PQS-controlled genes in the absence of PqsR and PQS. Our data also suggest that the regulatory activity of PqsE requires RhlR and indicate that a pqsE mutant can be complemented for pyocyanin production by a large excess of exogenous N-butyryl homoserine lactone (C4-HSL). Finally, we show that PqsE enhances the ability of Escherichia coli expressing RhlR to respond to C4-HSL. Overall, our data lead us to conclude that PqsE functions as a regulator that is independent of PqsR and PQS but dependent on the rhl quorum-sensing system.

scholarly journals The fitness ofPseudomonas aeruginosaquorum sensing signal cheats is influenced by the diffusivity of the environment

2016 ◽  
Author(s):  
Anne Mund ◽  
Stephen P. Diggle ◽  
Freya Harrison
Keyword(s):  
Quorum Sensing ◽  
Public Goods ◽  
Social Dynamics ◽  
Population Level ◽  
Opportunistic Pathogen ◽  
Signal Molecules ◽  
Wild Type ◽  
Signaling Systems ◽  
Environmental Structure ◽  
Bacterial Quorum

ABSTRACTExperiments examining the social dynamics of bacterial quorum sensing (QS) have focused on mutants which do not respond to signals, and the role of QS-regulated exoproducts as public goods. The potential for QS signal molecules to themselves be social public goods has received much less attention. Here, we analyse how signal-deficient (lasI−) mutants of the opportunistic pathogenPseudomonas aeruginosainteract with wild-type cells in an environment where QS is required for growth. We show that when growth requires a ‘private’ intracellular metabolic mechanism activated by the presence of QS signal,lasI−mutants act as social cheats and outcompete signal-producing wild-type bacteria in mixed cultures, because they can use the signals produced by wild type cells. However, reducing the ability of signal molecules to diffuse through the growth medium, results in signal molecules becoming less accessible to mutants, leading to reduced cheating. Our results indicate that QS signal molecules can be considered as social public goods in a way that has been previously described for other exoproducts, but that spatial structuring of populations reduces exploitation by non-cooperative signal cheats.ImportanceBacteria communicate via signaling molecules to regulate the expression of a whole range of genes. This process, termed quorum sensing (QS), moderates bacterial metabolism in many environmental conditions, from soil and water (where QS-regulated genes influence nutrient cycling) to animal hosts (where QS-regulated genes determine pathogen virulence). Understanding the ecology of QS could therefore yield vital clues as to how we might modify bacterial behaviour for environmental or clinical gains. Here, we demonstrate that QS signals act as shareable public goods. This means that their evolution, and therefore population-level responses to interference with QS, will be constrained by population structure. Further, we show that environmental structure (constraints on signal diffusion) alters the accessibility of QS signals and demonstrates that we need to consider population and environmental structure to help us further our understanding of QS signaling systems.

scholarly journals Phenylacetyl-CoA, not phenylacetic acid, attenuates CepIR-regulated virulence in Burkholderia cenocepacia

2019 ◽  
Author(s):  
Tasia Joy Lightly ◽  
Kara L. Frejuk ◽  
Marie-Christine Groleau ◽  
Laurent R. Chiarelli ◽  
Cor Ras ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Phenylacetic Acid ◽  
Tca Cycle ◽  
Opportunistic Pathogen ◽  
Degradation Pathway ◽  
Burkholderia Cenocepacia ◽  
Signal Molecules ◽  
Wild Type ◽  
Opportunistic Bacteria ◽  
Virulent Phenotype

AbstractDuring phenylalanine catabolism, phenylacetic acid (PAA) is converted to phenylacetyl-CoA (PAA-CoA) by a ligase, PaaK, and then epoxidized by a multicomponent monooxygenase, PaaABCDE, before further degradation to the TCA cycle. In the opportunistic pathogen Burkholderia cenocepacia, loss of paaABCDE attenuates virulence factor expression, which is under control of the LuxIR-like quorum sensing system, CepIR. To further investigate the link between CepIR-regulated virulence and PAA catabolism, we created knockout mutants of the first step of the pathway (PAA-CoA synthesis by PaaK) and characterized them in comparison to a paaABCDE mutant using liquid chromatography/mass spectrometry (LC-MS/MS) and virulence assays. We found that while loss of PaaABCDE decreased virulence, deletion of the paaK genes resulted in a more virulent phenotype than the wild type strain. Deletion of either paaK or paaABCDE led to higher levels of released PAA but no differences in internal accumulation, compared to wild type. While we found no evidence of direct cepIR downregulation by PAA-CoA or PAA, a low virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. On the other hand, removal of paaABCDE in the cepR mutant did not impact its attenuated phenotype. Together, our results suggest an indirect role for PAA-CoA in supressing B. cenocepacia CepIR-activated virulence.ImportanceThe opportunistic pathogen Burkholderia cenocepacia uses a chemical signal process called quorum sensing (QS) to produce virulence factors. In B. cenocepacia, QS relies on the presence of the transcriptional regulator CepR, which upon binding QS signal molecules, activates virulence. In this work, we found that even in the absence of CepR, B. cenocepacia can elicit a pathogenic response if phenylacetyl-CoA, an intermediate of the phenylacetic acid degradation pathway, is not produced. Instead, accumulation of phenylacetyl-CoA appears to attenuate pathogenicity. Therefore, we have discovered that it is possible to trigger virulence in the absence of CepR, challenging the classical view of activation of virulence by this QS mechanism. Our work provides new insight into the relationship between metabolism and virulence in opportunistic bacteria. We propose that, in the event that QS signaling molecules cannot accumulate to trigger a pathogenic response, a metabolic signal can still activate virulence in B. cenocepacia.

scholarly journals The Pseudomonas Quinolone Signal Regulates rhl Quorum Sensing in Pseudomonas aeruginosa

2000 ◽  
Vol 182 (10) ◽  
pp. 2702-2708 ◽  
Author(s):  
Susan L. McKnight ◽  
Barbara H. Iglewski ◽  
Everett C. Pesci
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Sensing System ◽  
Sensing Systems ◽  
Pseudomonas Quinolone Signal ◽  
Quorum Sensing System ◽  
Encoding Gene

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa uses intercellular signals to control the density-dependent expression of many virulence factors. The las and rhlquorum-sensing systems function, respectively, through the autoinducersN-(3-oxododecanoyl)-l-homoserine lactone andN-butyryl-l-homoserine lactone (C4-HSL), which are known to positively regulate the transcription of the elastase-encoding gene, lasB. Recently, we reported that a second type of intercellular signal is involved in lasB induction. This signal was identified as 2-heptyl-3-hydroxy-4-quinolone and designated thePseudomonas quinolone signal (PQS). PQS was determined to be part of the quorum-sensing hierarchy since its production and bioactivity depended on the las and rhlquorum-sensing systems, respectively. In order to define the role of PQS in the P. aeruginosa quorum-sensing cascade,lacZ gene fusions were used to determine the effect of PQS on the transcription of the quorum-sensing system geneslasR, lasI, rhlR, andrhlI. We found that in P. aeruginosa, PQS caused a major induction of rhlI′-lacZ and had lesser effects on the transcription of lasR′-lacZ andrhlR′-lacZ. We also observed that the transcription of bothrhlI′-lacZ and lasB′-lacZ was cooperatively effected by C4-HSL and PQS. Additionally, we present data indicating that PQS was not produced maximally until cultures reached the late stationary phase of growth. Taken together, our results imply that PQS acts as a link between the las and rhlquorum-sensing systems and that this signal is not involved in sensing cell density.

scholarly journals Full Virulence ofPseudomonas aeruginosaRequires OprF

2010 ◽  
Vol 79 (3) ◽  
pp. 1176-1186 ◽  
Author(s):  
Laurène Fito-Boncompte ◽  
Annelise Chapalain ◽  
Emeline Bouffartigues ◽  
Hichem Chaker ◽  
Olivier Lesouhaitier ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Signal Molecules ◽  
Animal Cells ◽  
Outer Membrane Porin ◽  
Lung Infections ◽  
The Comparative Study ◽  
Hospital Acquired ◽  
Virulence Factor Production

ABSTRACTOprF is a general outer membrane porin ofPseudomonas aeruginosa, a well-known human opportunistic pathogen associated with severe hospital-acquired sepsis and chronic lung infections of cystic fibrosis patients. A multiphenotypic approach, based on the comparative study of a wild-type strain ofP. aeruginosa, its isogenicoprFmutant, and anoprF-complemented strain, showed that OprF is required forP. aeruginosavirulence. The absence of OprF results in impaired adhesion to animal cells, secretion of ExoT and ExoS toxins through the type III secretion system (T3SS), and production of the quorum-sensing-dependent virulence factors pyocyanin, elastase, lectin PA-1L, and exotoxin A. Accordingly, in theoprFmutant, production of the signal moleculesN-(3-oxododecanoyl)-l-homoserine lactone andN-butanoyl-l-homoserine lactone was found to be reduced and delayed, respectively.Pseudomonasquinolone signal (PQS) production was decreased, while its precursor, 4-hydroxy-2-heptylquinoline (HHQ), accumulated in the cells. Taken together, these results show the involvement of OprF inP. aeruginosavirulence, at least partly through modulation of the quorum-sensing network. This is the first study showing a link between OprF, PQS synthesis, T3SS, and virulence factor production, providing novel insights into virulence expression.

scholarly journals Bacterial quorum sensing allows graded responses to variations in density, on both individual and population scales

2019 ◽  
Author(s):  
Jennifer Rattray ◽  
Stephen Thomas ◽  
Yifei Wang ◽  
Sam P. Brown
Keyword(s):  
Quorum Sensing ◽  
Cell Mass ◽  
Cell Communication ◽  
Reaction Norms ◽  
Signal Molecules ◽  
Standard View ◽  
Functional Studies ◽  
Graded Responses ◽  
Bacterial Quorum ◽  
The Individual

ABSTRACTQuorum sensing (QS) is a mechanism of cell-to-cell communication via diffusible signal molecules that controls multiple secreted factors including virulence factors in bacterial pathogens [1,2]. While the standard view is that QS functions as a density-sensing mechanism, the functional and evolutionary context of QS continues to be disputed [3–11]. A critical step in assessing the various adaptive hypotheses is establishing the functional capacities and limits of QS. Current functional studies largely focus on a dichotomy of QS on/off (or, quorate / sub-quorate) states, despite the increasing amount of heterogeneity on a cellular scale [4,12–16], overlooking the potential for intermediate, graded responses. In this paper we explore the functional capacity of QS to resolve finely graded environmental densities and introduce the use of reaction norms as a way to holistically characterize QS response. Here we show that Pseudomonas aeruginosa can deliver a graded response to variation in environmental population density on both the population and individual scales. We further resolve the linear population response to be the product of two component cellular reaction norms: the likelihood of being responsive and the intensity of response. Overall, this work reveals that there is no critical cell mass or ‘quorum’, at which QS is activated on either the individual cell or population scale.

scholarly journals Inhibition of quorum sensing in Pseudomonas aeruginosa by azithromycin and its effectiveness in urinary tract infections

2011 ◽  
Vol 60 (3) ◽  
pp. 300-306 ◽  
Author(s):  
Anju Bala ◽  
Ravi Kumar ◽  
Kusum Harjai
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Urinary Tract ◽  
Quorum Sensing ◽  
Urinary Tract Infections ◽  
Opportunistic Pathogen ◽  
Signal Molecules ◽  
Chronic Infections ◽  
Beneficial Effects ◽  
Tract Infections

Pseudomonas aeruginosa, an opportunistic pathogen, is the third most common pathogen associated with nosocomial urinary tract infections (UTIs). The virulence of this organism is due to its ability to produce quorum-sensing (QS) signal molecules and form biofilms. These biofilms are usually resistant to conventional antibiotics and host immune responses. Recently, beneficial effects of macrolides, especially azithromycin (AZM), have been shown in patients suffering from chronic infections caused by P. aeruginosa. These were due to anti-inflammatory and modulatory effects of AZM on the expression of virulence factors of this pathogen. The present study was designed to evaluate the potential of AZM to inhibit QS signal molecules and its ability to attenuate the virulence of P. aeruginosa in an experimental UTI model. Sub-MIC concentrations of AZM significantly inhibited the production of QS signals, swimming, swarming and twitching motilities, and biofilm formation in vitro. The therapeutic evaluation of AZM in this experimental UTI model showed complete clearance of the organisms from the mouse kidneys. The results of this study highlight the potential effectiveness of AZM in attenuating the virulence of P. aeruginosa in a UTI model.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

scholarly journals A Bacterial Tower of Babel: Quorum-Sensing Signaling Diversity and Its Evolution

2020 ◽  
Vol 74 (1) ◽  
pp. 587-606 ◽  
Author(s):  
Nitzan Aframian ◽  
Avigdor Eldar
Keyword(s):  
Quorum Sensing ◽  
Social Interactions ◽  
Signal Molecules ◽  
Allelic Polymorphism ◽  
Dependent Manner ◽  
Tower Of Babel ◽  
Cognate Receptor ◽  
Wide Range ◽  
Family Code ◽  
Bacterial Groups

Quorum sensing is a process in which bacteria secrete and sense a diffusible molecule, thereby enabling bacterial groups to coordinate their behavior in a density-dependent manner. Quorum sensing has evolved multiple times independently, utilizing different molecular pathways and signaling molecules. A common theme among many quorum-sensing families is their wide range of signaling diversity—different variants within a family code for different signal molecules with a cognate receptor specific to each variant. This pattern of vast allelic polymorphism raises several questions—How do different signaling variants interact with one another? How is this diversity maintained? And how did it come to exist in the first place? Here we argue that social interactions between signaling variants can explain the emergence and persistence of signaling diversity throughout evolution. Finally, we extend the discussion to include cases where multiple diverse systems work in concert in a single bacterium.

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