Computer-Aided Identification of Recognized Drugs as Pseudomonas aeruginosa Quorum-Sensing Inhibitors

ABSTRACT Attenuation of Pseudomonas aeruginosa virulence by the use of small-molecule quorum-sensing inhibitors (referred to as the antipathogenic drug principle) is likely to play a role in future treatment strategies for chronic infections. In this study, structure-based virtual screening was used in a search for putative quorum-sensing inhibitors from a database comprising approved drugs and natural compounds. The database was built from compounds which showed structural similarities to previously reported quorum-sensing inhibitors, the ligand of the P. aeruginosa quorum-sensing receptor LasR, and a quorum-sensing receptor agonist. Six top-ranking compounds, all recognized drugs, were identified and tested for quorum-sensing-inhibitory activity. Three compounds, salicylic acid, nifuroxazide, and chlorzoxazone, showed significant inhibition of quorum-sensing-regulated gene expression and related phenotypes in a dose-dependent manner. These results suggest that the identified compounds have the potential to be used as antipathogenic drugs. Furthermore, the results indicate that structure-based virtual screening is an efficient tool in the search for novel compounds to combat bacterial infections.

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Energy-Optimized Pharmacophore Coupled Virtual Screening in the Discovery of Quorum Sensing Inhibitors of LasR Protein of Pseudomonas aeruginosa

10.20944/preprints201910.0074.v1 ◽

2019 ◽

Author(s):

Zulkar Nain ◽

Sifat Bin Sayed ◽

Mohammad Minnatul Karim ◽

Md. Ariful Islam ◽

Utpal Kumar Adhikari

Keyword(s):

Pseudomonas Aeruginosa ◽

Virtual Screening ◽

Quorum Sensing ◽

Bacterial Infections ◽

Opportunistic Pathogen ◽

Vital Role ◽

Energy Calculation ◽

Quorum Sensing Inhibitors ◽

Binding Energy Calculation ◽

Standard Precision

Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Attenuation of virulence by QS inhibition could be an alternative and effective approach to control infections. Therefore, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. E-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs due to their higher binding affinity to LasR receptor (-7.53 to -10.32 kcal/mol compared to -7.43 kcal/mol of native ligands). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed good binding stability and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections.

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Identification of Five Structurally Unrelated Quorum-Sensing Inhibitors of Pseudomonas aeruginosa from a Natural-Derivative Database

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00955-13 ◽

2013 ◽

Vol 57 (11) ◽

pp. 5629-5641 ◽

Cited By ~ 57

Author(s):

Sean Yang-Yi Tan ◽

Song-Lin Chua ◽

Yicai Chen ◽

Scott A. Rice ◽

Staffan Kjelleberg ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Virulence Factors ◽

Extracellular Dna ◽

Signal Molecules ◽

Dependent Manner ◽

Absolute Quantitation ◽

Content Type ◽

Quorum Sensing Inhibitors ◽

Regulated Gene Expression

ABSTRACTBacteria communicate by means of small signal molecules in a process termed quorum sensing (QS). QS enables bacteria to organize their activities at the population level, including the coordinated secretion of virulence factors. Certain small-molecule compounds, known as quorum-sensing inhibitors (QSIs), have been shown to effectively block QS and subsequently attenuate the virulence ofPseudomonas aeruginosa, as well as increasing its susceptibility to both antibiotics and the immune system. In this study, a structure-based virtual screening (SB-VS) approach was used for the discovery of novel QSI candidates. Three-dimensional structures of 3,040 natural compounds and their derivatives were obtained, after which molecular docking was performed using the QS receptor LasR as a target. Based on docking scores and molecular masses, 22 compounds were purchased to determine their efficacies as quorum-sensing inhibitors. Using a live reporter assay for quorum sensing, 5 compounds were found to be able to inhibit QS-regulated gene expression inP. aeruginosain a dose-dependent manner. The most promising compound, G1, was evaluated by isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic analysis, and it was found to significantly affect the abundance of 46 proteins (19 were upregulated; 27 were downregulated) inP. aeruginosaPAO1. It specifically reduced the expression of several quorum-sensing-regulated virulence factors, such as protease IV, chitinase, and pyoverdine synthetases. G1 was also able to reduce extracellular DNA release and inhibited the secretion of the virulence factor, elastase, whose expression is regulated by LasR. These results demonstrate the utility of SB-VS for the discovery of target-specific QSIs.

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The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa

Journal of Bacteriology ◽

10.1128/jb.00444-21 ◽

2022 ◽

Author(s):

Michelle R. Scribner ◽

Amelia C. Stephens ◽

Justin L. Huong ◽

Anthony R. Richardson ◽

Vaughn S. Cooper

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Dependent Manner ◽

Chronic Infections ◽

Concentration Dependent Manner ◽

Surface Attachment ◽

Bacterial Populations ◽

Simple Medium ◽

Associated Conditions

The evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA , encoding a regulator of biofilm formation, or lasR , encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF . These findings demonstrate that nutrient conditions and biofilm selection are sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing. Importance Pseudomonas aeruginosa produces dangerous chronic infections that are known for their rapid diversification and recalcitrance to treatment. We performed evolution experiments to identify adaptations selected by two specific aspects of the CF respiratory environment: nutrient levels and surface attachment. Propagation of P. aeruginosa in nutrients present within the CF airway was sufficient to drive diversification into subpopulations with identical mutations in regulators of biofilm and quorum sensing to those arising during infection. Thus, the adaptation of opportunistic pathogens to nutrients found in the host may select mutants with phenotypes that complicate treatment and clearance of infection.

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The nutritional environment is sufficient to select coexisting biofilm and quorum-sensing mutants of Pseudomonas aeruginosa

10.1101/2021.09.01.458652 ◽

2021 ◽

Author(s):

Michelle R Scribner ◽

Amelia Carole Stephens ◽

Justin L Huong ◽

Anthony R. Richardson ◽

Vaughn S Cooper

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Dependent Manner ◽

Chronic Infections ◽

Concentration Dependent Manner ◽

Bacterial Populations ◽

Simple Medium ◽

Associated Conditions ◽

Nutritional Environment

The evolution of bacterial populations during infections can be influenced by various factors including available nutrients, the immune system, and competing microbes, rendering it difficult to identify the specific forces that select on evolved traits. The genomes of Pseudomonas aeruginosa isolated from the airway of patients with cystic fibrosis (CF), for example, have revealed commonly mutated genes, but which phenotypes led to their prevalence is often uncertain. Here, we focus on effects of nutritional components of the CF airway on genetic adaptations by P. aeruginosa grown in either well-mixed (planktonic) or biofilm-associated conditions. After only 80 generations of experimental evolution in a simple medium with glucose, lactate, and amino acids, all planktonic populations diversified into lineages with mutated genes common to CF infections: morA, encoding a regulator of biofilm formation, or lasR, encoding a quorum sensing regulator that modulates the expression of virulence factors. Although mutated quorum sensing is often thought to be selected in vivo due to altered virulence phenotypes or social cheating, isolates with lasR mutations demonstrated increased fitness when grown alone and outcompeted the ancestral PA14 strain. Nonsynonymous SNPs in morA increased fitness in a nutrient concentration-dependent manner during planktonic growth and surprisingly also increased biofilm production. Populations propagated in biofilm conditions also acquired mutations in loci associated with chronic infections, including lasR and cyclic-di-GMP regulators roeA and wspF. These findings demonstrate that nutrient conditions and biofilm selection are alone sufficient to select mutants with problematic clinical phenotypes including increased biofilm and altered quorum sensing.

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Production of Quorum Sensing Inhibitors in Growing Onion Bulbs Infected with Pseudomonas aeruginosa E (HQ324110)

ISRN Microbiology ◽

10.5402/2012/161890 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Mohamed H. Abd-Alla ◽

Shymaa R. Bashandy

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Virulence Factors ◽

Bacterial Growth ◽

Myristic Acid ◽

Bacterial Infections ◽

Strong Support ◽

New Approach ◽

Onion Bulbs ◽

Quorum Sensing Inhibitors

Eighteen organic compounds were present in growing onion bulbs cultivar Giza 6 infected with P. aeruginosa, but only fourteen of them are present in dry infected onion bulbs; however, four compounds were missing in dry onion. The missing compounds in dry infected onion bulbs are pantolactone, 4,5-dihydro-4,5-dimethylfuran-2(3H)-one, myristic acid, and linoleic acid. All of them were detected in growing onion (living cell) during Pseudomonas aeruginosa infection, and it is hypothesized that it may be produced by plants and act as defence system. Pantolactone and myristic acid were selected to explore their effects on growth and virulence factors of Pseudomonas aeruginosa. Exogenous application of pantolactone and myristic acid significantly inhibited pyocyanin production, protease, and lipase and polygalacturonase activity but did not have any significant effects on bacterial growth. The inhibition of virulence factors without reduction in bacterial growth may be providing strong support that these chemical molecules are general quorum sensing inhibitors than an antibacterial effect. Disruption of quorum sensing of pathogen indicates that this new approach has potential in fighting bacterial infections in human and plants.

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Structure based virtual screening for identification of potential quorum sensing inhibitors against LasR master regulator in Pseudomonas aeruginosa

Microbial Pathogenesis ◽

10.1016/j.micpath.2017.03.026 ◽

2017 ◽

Vol 107 ◽

pp. 136-143 ◽

Cited By ~ 17

Author(s):

Manmohit Kalia ◽

Pradeep Kumar Singh ◽

Vivek Kumar Yadav ◽

Birendra Singh Yadav ◽

Deepmala Sharma ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Virtual Screening ◽

Quorum Sensing ◽

Master Regulator ◽

Quorum Sensing Inhibitors

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Energy-optimized pharmacophore coupled virtual screening in the discovery of quorum sensing inhibitors of LasR protein of Pseudomonas aeruginosa

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1700168 ◽

2019 ◽

Vol 38 (18) ◽

pp. 5374-5388 ◽

Cited By ~ 4

Author(s):

Zulkar Nain ◽

Sifat Bin Sayed ◽

Mohammad Minnatul Karim ◽

Md Ariful Islam ◽

Utpal Kumar Adhikari

Keyword(s):

Pseudomonas Aeruginosa ◽

Virtual Screening ◽

Quorum Sensing ◽

Quorum Sensing Inhibitors

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Polyphenols from Salix tetrasperma Impair Virulence and Inhibit Quorum Sensing of Pseudomonas aeruginosa

Molecules ◽

10.3390/molecules25061341 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1341 ◽

Cited By ~ 4

Author(s):

Islam Mostafa ◽

Hisham A. Abbas ◽

Mohamed L. Ashour ◽

Abdelaziz Yasri ◽

Assem M. El-Shazly ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Secondary Metabolites ◽

Bacterial Resistance ◽

Stem Bark ◽

Dependent Manner ◽

Active Components ◽

Quorum Sensing Inhibitors ◽

Bacterial Quorum Sensing ◽

Bacterial Quorum

Bacterial resistance represents one of the emerging obstacles in plants, animals, and humans that impairs treatment with antibacterial agents. Targeting of the bacterial quorum sensing system is one of the strategies to overcome this problem. Recently, research has been focused on natural and food components which can function as quorum sensing inhibitors. In this study, a methanol extract from Salix tetrasperma stem bark was phytochemically profiled by LC-MS analysis. This resulted in the identification of 38 secondary metabolites with (epi)catechin-(epi)catechin, epicatechin, tremulacin, salicortin, and trichocarposide as the major constituents. The extracts of both stem bark and the previously profiled flower of S. tetrasperma were tested for anti-quorum sensing activity in a common and widely distributed pathogen Pseudomonas aeruginosa. The natural products inhibited swimming and swarming motilities, as well as proteolytic and hemolytic activities in a dose-dependent manner. Molecular docking of the constituents from both extracts against the quorum sensing controlling systems Lasl/LasR, rhll/rhlR, and PQS/MvfR showed that epicatechin, (epi)catechin-(epi)catechin, p-hydroxy benzoyl galloyl glucose, p-hydroxy benzoyl protocatechuic acid glucose, and caffeoylmalic acid could be the main active components. This study supports the importance of secondary metabolites, especially polyphenols, as quorum sensing inhibitors.

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