Molecular insight into the activity of LasR protein from Pseudomonas aeruginosa in the regulation of virulence gene expression by this organism

Chowdhury, Nilkanta; Bagchi, Angshuman

doi:10.1016/j.gene.2015.12.067

Cited by 29 publications

(28 citation statements)

References 19 publications

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“…Interestingly, SNPs in the same position (V208) have been identified in P. aeruginosa isolates collected from CF sputum samples (39). V208 is adjacent to the D209 residue in the LasR DNA-binding domain (57,58), suggesting an impact on the structure of LasR and its DNA binding affinity. We assessed the impact of lasR V208G SNP frequency on changes on two QS-dependent phenotypic traits; production of 3O-C12-HSL signal and total protease.…”

Section: Genomic Variation In Evolving Biofilm Populations Over 50 Damentioning

confidence: 99%

Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations

Azimi

Roberts

Peng

et al. 2019

Preprint

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AbstractPseudomonas aeruginosa is an opportunistic pathogen that chronically infects the lungs of individuals with cystic fibrosis (CF) by forming antibiotic resistant biofilms. Emergence of phenotypically diverse isolates within CF P. aeruginosa populations has previously been reported, however, the impact of heterogeneity on social behaviors and community function is poorly understood. Here we describe how this heterogeneity impacts on behavioral traits by evolving the strain PAO1 in biofilms grown in a synthetic sputum medium for 50 days. We measured social trait production and antibiotic tolerance and used a metagenomic approach to analyze and assess genomic changes over the duration of the evolution experiment. We found that (i) evolutionary trajectories were reproducible in independently evolving populations; (ii) over 60% of genomic diversity occurred within the first 10 days of selection. We then focused on quorum sensing (QS), a well-studied P. aeruginosa trait that is commonly mutated in strains isolated from CF lungs. We found that at the population level (i) evolution in sputum medium selected for decreased production of QS and QS-dependent traits; (ii) there was a significant correlation between lasR mutant frequency, the loss of protease and the 3O-C12-HSL signal, and an increase in resistance to clinically relevant β-lactam antibiotics, despite no previous antibiotic exposure. Overall, our findings provide insights into the effect of allelic polymorphism on community functions in diverse P. aeruginosa populations. Further, we demonstrate that P. aeruginosa population and evolutionary dynamics can impact on traits important for virulence and can lead to increased tolerance to β-lactam antibiotics.

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Section: Genomic Variation In Evolving Biofilm Populations Over 50 Damentioning

confidence: 99%

Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations

Azimi

Roberts

Peng

et al. 2019

Preprint

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“…Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative, monoflagellated, obligatory aerobic bacteria (1,2). It can be found in many diverse environments such as soil, plants, hospitals, etc.…”

Section: Introductionmentioning

confidence: 99%

“…It can be found in many diverse environments such as soil, plants, hospitals, etc. (1,3). P. aeruginosa is an opportunistic human pathogen, because it rarely infects healthy persons.…”

Section: Introductionmentioning

confidence: 99%

“…The central problem is that it affects patients suffering from AIDS, cystic fibrosis, cancer and burn victims (2,4). Most of the deaths caused by cystic fibrosis are due to this pathogen (1,5). The pathogenicity of P.…”

Section: Introductionmentioning

confidence: 99%

“…Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative, monoflagellated, obligatory aerobic, Bacillus of the family Pseudomonadaceae and was first introduced at the end of the nineteenth century (1,2). It has been found in environments such as soil, water, in human bodies, in animals, sewage, plants, and hospitals (3).…”

Section: Introductionmentioning

confidence: 99%

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Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR ofPseudomonas aeruginosa: Insights from molecular docking and dynamics simulations

Grabski

Hunanyan

Tiratsuyan

et al. 2017

Preprint

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BackgroundIn 2017 World Health Organization announced the list of the most dangerous superbugs and among them is Pseudomonas aeruginosa, which is an antibiotic resistant opportunistic human pathogen as well as one of the ‘SKAPE’ pathogens. The central problem is that it affects patients suffering from AIDS, cystic fibrosis, cancer, burn victims etc. P. aeruginosa creates and inhabits surface-associated biofilms. Biofilms increase resistance to antibiotics and host immune responses, because of those current treatments are not effective. It is imperative to find new antibacterial treatment strategies against P. aeruginosa, but detailed molecular properties of the LasR protein are not clearly known to date. In the present study, we tried to analyse the molecular properties of the LasR protein as well as the mode of its interactions with autoinducer (AI) the N-3-oxododecanoyl homoserine lactone (3-0-C12-HSL).ResultsWe performed docking and molecular dynamics (MD) simulations of the LasR protein of P. aeruginosa with the 3-0-C12-HSL ligand. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of the 3-0-C12-HSL with LasR. A new interaction site of the 3-0-C12-HSL with LasR protein was found, which involves interaction with conservative residues from ligand binding domain (LBD), beta turns in the short linker region (SLR) and DNA binding domain (DBD). It will be referenced as the LBD-SLR-DBD bridge interaction or “the bridge”. We have also performed LasR monomer protein docking and found a new form of dimerization.ConclusionsThis study may offer new insights for future experimental studies to detect the interaction of the autoinducer with “the bridge” of LasR protein and a new interaction site for drug design.

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Identification of ligand binding activity and DNA recognition by RhlR protein from opportunistic pathogen Pseudomonas aeruginosa—a molecular dynamic simulation approach

Chowdhury

Bagchi

2018

J of Molecular Recognition

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RhlR protein from opportunistic pathogen Pseudomonas aeruginosa is involved in the transcription of virulence genes of the organism. The RhlR protein functions as a dimer and binds to the cognate promoter DNA with the help of an autoinducer ligand BHL to initiate the transcription of the virulence genes. Till date, there are no reports that detail the mechanism of virulence gene expression by RhlR protein in P. aeruginosa. In this work, we tried to analyse the molecular aspects of the various binding interactions of the RhlR protein while formimg the dimmer as well as with the promoter DNA. We analysed the mode of dimerisation of the RhlR protein and its binding interactions with the autoinducer BHL ligand. From our analyses, we could identify the potential amino acid residues which are involved in the binding interactions. We also predicted how the autoinducer BHL would help in making contacts with the DNA as well as with itself. Thus, the autoinducer BHL would serve as an important mediator of molecular interactions involved in binding the RhlR protein to itself as well as with the promoter DNA. Therefore, any other molecule which would be able to compete with the autoinducer ligand BHL to bind to RhlR protein but would not let the RhlR protein bind the promoter DNA would be an ideal drug candidate to prevent the transcription process of the virulence genes in P. aeruginosa. Our future aim is to predict suitable ligands which would compete with BHL to thwart the transcription process.

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Molecular insight into the activity of LasR protein from Pseudomonas aeruginosa in the regulation of virulence gene expression by this organism

Cited by 29 publications

References 19 publications

Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations

Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations

Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR ofPseudomonas aeruginosa: Insights from molecular docking and dynamics simulations

Identification of ligand binding activity and DNA recognition by RhlR protein from opportunistic pathogen Pseudomonas aeruginosa—a molecular dynamic simulation approach

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