scholarly journals Interaction of quercetin with transcriptional regulator LasR of Pseudomonas aeruginosa: Mechanistic insights of the inhibition of virulence through quorum sensing

2017 ◽  
Author(s):  
Hovakim Grabski ◽  
Lernik Hunanyan ◽  
Susanna Tiratsuyan ◽  
Hrachik Vardapetyan
Keyword(s):  
Molecular Dynamics ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Principal Component ◽  
Transcriptional Regulator ◽  
Binding Mode ◽  
World Health ◽  
Hydroxyl Group ◽  
Binding Modes

ABSTRACTBackgroundPseudomonas aeruginosais one of the most dangerous superbugs in the list of bacteria for which new antibiotics are urgently needed, which was published by World Health Organization.P. aeruginosais an antibiotic-resistant opportunistic human pathogen. It affects patients with AIDS, cystic fibrosis, cancer, burn victims and people with prosthetics and implants.P. aeruginosaalso forms biofilms. Biofilms increase resistance to antibiotics and host immune responses. Because of biofilms, current therapies are not effective. It is important to find new antibacterial treatment strategies againstP. aeruginosa. Biofilm formation is regulated through a system called quorum sensing. Thus disrupting this system is considered a promising strategy to combat bacterial pathogenicity. It is known that quercetin inhibitsPseudomonas aeruginosabiofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with quercetin.ResultsWe used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques for the study of the interaction of the LasR protein ofP. aeruginosawith quercetin. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of quercetin with LasR. We show that quercetin has two binding modes. One binding mode is the interaction with ligand binding domain, this interaction is not competitive and it has also been shown experimentally. The second binding mode is the interaction with the bridge, it involves conservative amino acid interactions from LBD, SLR, and DBD and it is also not competitive. Experimental studies show hydroxyl group of ring A is necessary for inhibitory activity, in our model the hydroxyl group interacts with Leu177 during the second binding mode. This could explain the molecular mechanism of how quercetin inhibits LasR protein.ConclusionsThis study may offer insights on how quercetin inhibits quorum sensing circuitry by interacting with transcriptional regulator LasR. The capability of having two binding modes may explain why quercetin is effective at inhibiting biofilm formation and virulence gene expression.List of abbreviationsPDBProtein data bankMDMolecular DynamicsPCAPrincipal Component AnalysisPCPrincipal ComponentSLRShort Linker RegionBLASTBasic local alignment search toolDBIDavid-Bouldin IndexpsFpseudo-F statistic

scholarly journals Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR

2018 ◽  
Author(s):  
Hovakim Grabski ◽  
Susanna Tiratsuyan
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Principal Component ◽  
Binding Mode ◽  
Machine Learning Techniques ◽  
Hydroxyl Group ◽  
Binding Modes ◽  
And Cluster Analysis ◽  
Dynamics Simulations

Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.

scholarly journals PqsE Is Essential for RhlR-Dependent Quorum Sensing Regulation in Pseudomonas aeruginosa

mSystems ◽  
2020 ◽  
Vol 5 (3) ◽  
Author(s):  
Marie-Christine Groleau ◽  
Thays de Oliveira Pereira ◽  
Valérie Dekimpe ◽  
Eric Déziel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Cell Communication ◽  
Transcriptional Regulator ◽  
Homoserine Lactone ◽  
World Health ◽  
Chronic Infections ◽  
Content Type ◽  
Main Regulator ◽  
Health Organization

ABSTRACT The bacterium Pseudomonas aeruginosa has emerged as a central threat in health care settings and can cause a large variety of infections. It expresses an arsenal of virulence factors and a diversity of survival functions, many of which are finely and tightly regulated by an intricate circuitry of three quorum sensing (QS) systems. The las system is considered at the top of the QS hierarchy and activates the rhl and pqs systems. It is composed of the LasR transcriptional regulator and the LasI autoinducer synthase, which produces 3-oxo-C12-homoserine lactone (3-oxo-C12-HSL), the ligand of LasR. RhlR is the transcriptional regulator for the rhl system and is associated with RhlI, which produces its cognate autoinducer C4-HSL. The third QS system is composed of the pqsABCDE operon and the MvfR (PqsR) regulator. PqsABCD synthetize 4-hydroxy-2-alkylquinolines (HAQs), which include ligands activating MvfR. PqsE is not required for HAQ production and instead is associated with the expression of genes controlled by the rhl system. While RhlR is often considered the main regulator of rhlI, we confirmed that LasR is in fact the principal regulator of C4-HSL production and that RhlR regulates rhlI and production of C4-HSL essentially only in the absence of LasR by using liquid chromatography-mass spectrometry quantifications and gene expression reporters. Investigating the expression of RhlR targets also clarified that activation of RhlR-dependent QS relies on PqsE, especially when LasR is not functional. This work positions RhlR as the key QS regulator and points to PqsE as an essential effector for full activation of this regulation. IMPORTANCE Pseudomonas aeruginosa is a versatile bacterium found in various environments. It can cause severe infections in immunocompromised patients and naturally resists many antibiotics. The World Health Organization listed it among the top priority pathogens for research and development of new antimicrobial compounds. Quorum sensing (QS) is a cell-cell communication mechanism, which is important for P. aeruginosa adaptation and pathogenesis. Here, we validate the central role of the PqsE protein in QS particularly by its impact on the regulator RhlR. This study challenges the traditional dogmas of QS regulation in P. aeruginosa and ties loose ends in our understanding of the traditional QS circuit by confirming RhlR to be the main QS regulator in P. aeruginosa. PqsE could represent an ideal target for the development of new control methods against the virulence of P. aeruginosa. This is especially important when considering that LasR-defective mutants frequently arise, e.g., in chronic infections.

The outlier Pseudomonas aeruginosa strain ATCC 9027 harbors a defective LasR quorum-sensing transcriptional regulator

2020 ◽  
Vol 367 (16) ◽  
Author(s):  
Selene García-Reyes ◽  
Martín P Soto-Aceves ◽  
Miguel Cocotl-Yañez ◽  
Abigail González-Valdez ◽  
Luis Servín-González ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Transcriptional Regulator ◽  
World Health ◽  
Regulatory Sequences ◽  
Strain Atcc ◽  
Research Priority ◽  
Important Health ◽  
Clade 1 ◽  
Health Organization

ABSTRACT Pseudomonas aeruginosa infections represent an important health problem that has been recognized by the World Health Organization as a research priority. A complex regulatory network called the quorum sensing (QS) regulates several P. aeruginosa virulence-related traits, including production of elastase, rhamnolipids and pyocyanin. The avirulent P. aeruginosa strain ATCC 9027 belongs to clade 3, which is the more distant phylogroup in relationship to the other four clades of this species. This strain does not produce QS-regulated virulence factors such as elastase and rhamnolipids when cultured in rich LB medium. We report here that ATCC 9027 harbors a defective LasR protein, presumably due to the presence of an aspartic acid in position 196 instead of a glutamic acid which is the amino acid present in this position in functional LasR proteins of the type strains PAO1 (clade 1) and PA7 (also belonging to clade 3), among others. In addition, we report that ATCC 9027 and PA7 strains present differences compared to the PAO1 strain in lasB which encodes elastase, and in the rhlR regulatory sequences that modify las-boxes, and that these mutations have a little effect in the expression of these genes by a functional LasR transcriptional regulator.

scholarly journals Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 686 ◽  
Author(s):  
Alexander Neumann ◽  
Viktor Engel ◽  
Andhika B. Mahardhika ◽  
Clara T. Schoeder ◽  
Vigneshwaran Namasivayam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
G Protein ◽  
Phenyl Ring ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Binding Modes ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

scholarly journals Virtual Screening and Biological Evaluation of Anti-Biofilm Agents Targeting LuxS in the Quorum Sensing System

2021 ◽  
Vol 16 (6) ◽  
pp. 1934578X2110196
Author(s):  
Zheng Liu ◽  
Lihua Zhang ◽  
Jincai Wang ◽  
Yanping Li ◽  
Yiqun Chang ◽  
...  
Keyword(s):  
Dental Caries ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Oral Diseases ◽  
Traditional Use ◽  
New Approach ◽  
Sensing System ◽  
Plaque Biofilm

Biofilm formation is considered as a crucial factor in various oral diseases, such as dental caries. The quorum sensing (QS) signaling system was proved to have a crucial role in the microbial dental plaque biofilm formation of Streptococcus mutans ( S. mutans). LuxS was critical to regulating the QS system and survival of the bacterium, and, therefore, compounds which target LuxS may be a potential therapy for dental caries. The binding activities of 37,170 natural compounds to LuxS were virtually screened in this study. Baicalein and paeonol were chosen for further research of the binding mode and ΔG values with LuxS. Both baicalein and paeonol inhibited the biofilm formation without influence on the growth of S. mutans. Baicalein also distinctly reduced the production of both rhamnolipids and acids. The results provide us with a new approach to combat dental caries instead of the traditional use of antibacterial chemicals.

scholarly journals Revisiting the quorum-sensing hierarchy in Pseudomonas aeruginosa: the transcriptional regulator RhlR regulates LasR-specific factors

Microbiology ◽  
2009 ◽  
Vol 155 (3) ◽  
pp. 712-723 ◽  
Author(s):  
Valérie Dekimpe ◽  
Eric Déziel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Transcriptional Regulator ◽  
Homoserine Lactone ◽  
The Other ◽  
Virulence Determinants ◽  
Late Stationary Phase ◽  
Regulatory Systems ◽  
Specific Factors

Pseudomonas aeruginosa uses the two major quorum-sensing (QS) regulatory systems las and rhl to modulate the expression of many of its virulence factors. The las system is considered to stand at the top of the QS hierarchy. However, some virulence factors such as pyocyanin have been reported to still be produced in lasR mutants under certain conditions. Interestingly, such mutants arise spontaneously under various conditions, including in the airways of cystic fibrosis patients. Using transcriptional lacZ reporters, LC/MS quantification and phenotypic assays, we have investigated the regulation of QS-controlled factors by the las system. Our results show that activity of the rhl system is only delayed in a lasR mutant, thus allowing the expression of multiple virulence determinants such as pyocyanin, rhamnolipids and C4-homoserine lactone (HSL) during the late stationary phase. Moreover, at this stage, RhlR is able to overcome the absence of the las system by activating specific LasR-controlled functions, including production of 3-oxo-C12-HSL and Pseudomonas quinolone signal (PQS). P. aeruginosa is thus able to circumvent the deficiency of one of its QS systems by allowing the other to take over. This work demonstrates that the QS hierarchy is more complex than the model simply presenting the las system above the rhl system.

Inhibition of biofilm formation and quorum sensing mediated virulence in Pseudomonas aeruginosa by marine sponge symbiont Brevibacterium casei strain Alu 1

2021 ◽  
Vol 150 ◽  
pp. 104693
Author(s):  
Nagasundaram Rashiya ◽  
Nagarajan Padmini ◽  
Antony Alex Kennedy Ajilda ◽  
Pandiyan Prabakaran ◽  
Ravindran Durgadevi ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Marine Sponge ◽  
Biofilm Formation
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