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

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01283-08 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2432-2443 ◽

Cited By ~ 133

Author(s):

Liang Yang ◽

Morten Theil Rybtke ◽

Tim Holm Jakobsen ◽

Morten Hentzer ◽

Thomas Bjarnsholt ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Virtual Screening ◽

Quorum Sensing ◽

Bacterial Infections ◽

Treatment Strategies ◽

Significant Inhibition ◽

Dependent Manner ◽

Chronic Infections ◽

Quorum Sensing Inhibitors ◽

Regulated Gene Expression

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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Characterization of Pseudomonas aeruginosa Quorum Sensing Inhibitors from the Endophyte Lasiodiplodia venezuelensis and Evaluation of Their Antivirulence Effects by Metabolomics

Microorganisms ◽

10.3390/microorganisms9091807 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1807

Author(s):

Léonie Pellissier ◽

Sara Leoni ◽

Laurence Marcourt ◽

Emerson Ferreira Queiroz ◽

Nicole Lecoultre ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Virulence Factors ◽

Antimicrobial Agents ◽

Fungal Endophytes ◽

Opportunistic Pathogen ◽

Single Step ◽

Bioactive Natural Products ◽

Quorum Sensing Inhibitors ◽

Wide Range

The opportunistic pathogen Pseudomonas aeruginosa is one of the “critical priority pathogens” due to its multidrug resistance to a wide range of antibiotics. Its ability to invade and damage host tissues is due to the use of quorum sensing (QS) to collectively produce a plethora of virulence factors. Inhibition of QS is an attractive strategy for new antimicrobial agents because it disrupts the initial events of infection without killing the pathogen. Highly diverse microorganisms as endophytes represent an under-explored source of bioactive natural products, offering opportunities for the discovery of novel QS inhibitors (QSI). In the present work, the objective was to explore selective QSIs within a unique collection of fungal endophytes isolated from the tropical palm Astrocaryum sciophilum. The fungi were cultured, extracted, and screened for their antibacterial and specific anti-QS activities against P. aeruginosa. The endophytic strain Lasiodiplodia venezuelensis was prioritized for scaled-up fractionation for its selective activity, leading to the isolation of eight compounds in a single step. Among them, two pyran-derivatives were found to be responsible for the QSI activity, with an effect on some QS-regulated virulence factors. Additional non-targeted metabolomic studies on P. aeruginosa documented their effects on the production of various virulence-related metabolites.

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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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The effect of Quorum sensing inhibitors on the evolution of CRISPR-based phage immunity in Pseudomonas aeruginosa

The ISME Journal ◽

10.1038/s41396-021-00946-6 ◽

2021 ◽

Author(s):

Jenny M. Broniewski ◽

Matthew A. W. Chisnall ◽

Nina Molin Høyland-Kroghsbo ◽

Angus Buckling ◽

Edze R. Westra

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Evolutionary Dynamics ◽

Opportunistic Pathogen ◽

Specific Phage ◽

Type Iv ◽

Quorum Sensing Inhibitors ◽

Wide Range ◽

Chemical Inhibition ◽

Adsorption Rates

AbstractQuorum sensing controls the expression of a wide range of important traits in the opportunistic pathogen Pseudomonas aeruginosa, including the expression of virulence genes and its CRISPR-cas immune system, which protects from bacteriophage (phage) infection. This finding has led to the speculation that synthetic quorum sensing inhibitors could be used to limit the evolution of CRISPR immunity during phage therapy. Here we use experimental evolution to explore if and how a quorum sensing inhibitor influences the population and evolutionary dynamics of P. aeruginosa upon phage DMS3vir infection. We find that chemical inhibition of quorum sensing decreases phage adsorption rates due to downregulation of the Type IV pilus, which causes delayed lysis of bacterial cultures and favours the evolution of CRISPR immunity. Our data therefore suggest that inhibiting quorum sensing may reduce rather than improve the therapeutic efficacy of pilus-specific phage, and this is likely a general feature when phage receptors are positively regulated by quorum sensing.

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Traditional Chinese Medicine Tanreqing Inhibits Quorum Sensing Systems in Pseudomonas aeruginosa

Frontiers in Microbiology ◽

10.3389/fmicb.2020.517462 ◽

2020 ◽

Vol 11 ◽

Author(s):

Weifeng Yang ◽

Qing Wei ◽

Qian Tong ◽

Kaiyu Cui ◽

Gaiying He ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Quorum Sensing ◽

Virulence Factors ◽

Bacterial Infections ◽

Cell Communication ◽

Opportunistic Pathogen ◽

Communication Process ◽

Phenotypic Analysis

Pseudomonas aeruginosa is an opportunistic pathogen that can infect a wide variety of hosts including humans, plants, and animals. The production of virulence factors is the determinant of the infection paradigm and is under orchestrated regulation via cell-to-cell communication process called quorum sensing (QS). To disable QS circuits and prevent bacterial infections, a large battery of anti-QS agents, particularly from traditional Chinese medicine have been developed. Here, we used P. aeruginosa as a model microorganism to investigate the effect of traditional Chinese medicine Tanreqing (TRQ) formula on bacterial pathogenicity. Phenotypic analysis showed that TRQ treatment could completely inhibit the production of phenazine pyocyanin and moderately inhibit the production of virulence factors such as rhamnolipids, elastase, and alkaline protease. Further transcriptomic analyses revealed that TRQ treatment could significantly attenuate the expression of QS-regulated genes in P. aeruginosa and TRQ-treated P. aeruginosa regulon shared a large overlap with QS regulon. Component contribution to QS inhibition shed light on the indispensable role of all five components in TRQ formula. Further genetic analysis indicated that upstream regulators of QS systems, including two-component systems GacS/GacA and PprA/PprB, were both inhibited by TRQ treatment. Finally, our TRQ formula could efficiently protect Caenorhabditis elegans from killing by P. aeruginosa. Altogether, we have proved TRQ formula as an effective and specific agent to attenuate bacterial virulence and combat bacterial infections.

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Genetic and transcriptomic characteristics of RhlR-dependent quorum sensing in cystic fibrosis isolates of Pseudomonas aeruginosa

10.1101/2021.12.21.470774 ◽

2021 ◽

Author(s):

Kyle L Asfahl ◽

Nicole E Smalley ◽

Alexandria P Chang ◽

Ajai A Dandekar

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Bacterial Infections ◽

Opportunistic Pathogen ◽

Homoserine Lactone ◽

Signaling Mechanism ◽

Genetic Characteristics ◽

Genes Encoding ◽

A Cell

In people with the genetic disease cystic fibrosis (CF), bacterial infections involving the opportunistic pathogen Pseudomonas aeruginosa are a significant cause of morbidity and mortality. P. aeruginosa uses a cell-cell signaling mechanism called quorum sensing (QS) to regulate many virulence functions. One type of QS consists of acyl-homoserine lactone (AHL) signals produced by LuxI-type signal synthases, which bind a cognate LuxR-type transcription factor. In laboratory strains and conditions, P. aeruginosa employs two AHL synthase/receptor pairs arranged in a hierarchy, with the LasI/R system controlling the RhlI/R system and many downstream virulence factors. However, P. aeruginosa isolates with inactivating mutations in lasR are frequently isolated from chronic CF infections. We and others have shown that these isolates frequently use RhlR as the primary QS regulator. RhlR is rarely mutated in CF and environmental settings. We were interested if there were reproducible genetic characteristics of these isolates and if there was a central group of genes regulated by RhlR in all isolates. We examined five isolates and found signatures of adaptation common to CF isolates. We did not identify a common genetic mechanism to explain the switch from Las- to Rhl-dominated QS. We describe a core RhlR regulon encompassing 20 genes encoding 7 products. These results suggest a key group of QS-regulated factors important for pathogenesis of chronic infection, and position RhlR as a target for anti-QS therapeutics. Our work underscores the need to sample a diversity of isolates to understanding QS beyond what has been described in laboratory strains.

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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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Food as a Source for Quorum Sensing Inhibitors: Iberin from Horseradish Revealed as a Quorum Sensing Inhibitor of Pseudomonas aeruginosa

Applied and Environmental Microbiology ◽

10.1128/aem.05992-11 ◽

2012 ◽

Vol 78 (7) ◽

pp. 2410-2421 ◽

Cited By ~ 117

Author(s):

Tim Holm Jakobsen ◽

Steinn Kristinn Bragason ◽

Richard Kerry Phipps ◽

Louise Dahl Christensen ◽

Maria van Gennip ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Bacterial Infections ◽

Opportunistic Pathogen ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Array Detector ◽

Content Type ◽

Health Promoting ◽

Microarray Studies

ABSTRACTFoods with health-promoting effects beyond nutritional values have been gaining increasing research focus in recent years, although not much has been published on this subject in relation to bacterial infections. With respect to treatment, a novel antimicrobial strategy, which is expected to transcend problems with selective pressures for antibiotic resistance, is to interrupt bacterial communication, also known as quorum sensing (QS), by means of signal antagonists, the so-called QS inhibitors (QSIs). Furthermore, QSI agents offer a potential solution to the deficiencies associated with use of traditional antibiotics to treat infections caused by bacterial biofilms and multidrug-resistant bacteria. Several QSIs of natural origin have been identified, and in this study, several common food products and plants were extracted and screened for QSI activity in an attempt to isolate and characterize previously unknown QSI compounds active against the common opportunistic pathogenPseudomonas aeruginosa. Several extracts displayed activity, but horseradish exhibited the highest activity. Chromatographic separation led to the isolation of a potent QSI compound that was identified by liquid chromatography-diode array detector-mass spectrometry (LC-DAD-MS) and nuclear magnetic resonance (NMR) spectroscopy as iberin—an isothiocyanate produced by many members of theBrassicaceaefamily. Real-time PCR (RT-PCR) and DNA microarray studies showed that iberin specifically blocks expression of QS-regulated genes inP. aeruginosa.

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