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

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.

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

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.

scholarly journals Pseudomonas aeruginosa PA80 is a cystic fibrosis isolate deficient in RhlRI quorum sensing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Syed A. K. Shifat Ahmed ◽  
Michelle Rudden ◽  
Sabrina M. Elias ◽  
Thomas J. Smyth ◽  
Roger Marchant ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Genomic Islands ◽  
Clinical Strain ◽  
Whole Genome ◽  
Synonymous Mutations ◽  
Wide Range

AbstractPseudomonas aeruginosa uses quorum sensing (QS) to modulate the expression of several virulence factors that enable it to establish severe infections. The QS system in P. aeruginosa is complex, intricate and is dominated by two main N-acyl-homoserine lactone circuits, LasRI and RhlRI. These two QS systems work in a hierarchical fashion with LasRI at the top, directly regulating RhlRI. Together these QS circuits regulate several virulence associated genes, metabolites, and enzymes in P. aeruginosa. Paradoxically, LasR mutants are frequently isolated from chronic P. aeruginosa infections, typically among cystic fibrosis (CF) patients. This suggests P. aeruginosa can undergo significant evolutionary pathoadaptation to persist in long term chronic infections. In contrast, mutations in the RhlRI system are less common. Here, we have isolated a clinical strain of P. aeruginosa from a CF patient that has deleted the transcriptional regulator RhlR entirely. Whole genome sequencing shows the rhlR locus is deleted in PA80 alongside a few non-synonymous mutations in virulence factors including protease lasA and rhamnolipid rhlA, rhlB, rhlC. Importantly we did not observe any mutations in the LasRI QS system. PA80 does not appear to have an accumulation of mutations typically associated with several hallmark pathoadaptive genes (i.e., mexT, mucA, algR, rpoN, exsS, ampR). Whole genome comparisons show that P. aeruginosa strain PA80 is closely related to the hypervirulent Liverpool epidemic strain (LES) LESB58. PA80 also contains several genomic islands (GI’s) encoding virulence and/or resistance determinants homologous to LESB58. To further understand the effect of these mutations in PA80 QS regulatory and virulence associated genes, we compared transcriptional expression of genes and phenotypic effects with isogenic mutants in the genetic reference strain PAO1. In PAO1, we show that deletion of rhlR has a much more significant impact on the expression of a wide range of virulence associated factors rather than deletion of lasR. In PA80, no QS regulatory genes were expressed, which we attribute to the inactivation of the RhlRI QS system by deletion of rhlR and mutation of rhlI. This study demonstrates that inactivation of the LasRI system does not impact RhlRI regulated virulence factors. PA80 has bypassed the common pathoadaptive mutations observed in LasR by targeting the RhlRI system. This suggests that RhlRI is a significant target for the long-term persistence of P. aeruginosa in chronic CF patients. This raises important questions in targeting QS systems for therapeutic interventions.

scholarly journals Plantain Herb Extracts significantly attenuate the quorum sensing-controlled virulence factors and inhibit biofilm formation in Pseudomonas aeruginosa PAO1

2019 ◽  
Vol 78 ◽  
pp. 01004
Author(s):  
Shan Li ◽  
Jiangning Yao ◽  
Haoming Li
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Significant Inhibition ◽  
Control Group ◽  
Produce Cell ◽  
Group B ◽  
Herb Extracts

Pseudomonas aeruginosa is a Gram-negative organism that can survive under harsh conditions, and it is also an opportunistic pathogen that can produce cell-associated extracellular virulence factors. Several of these virulence factors have been demonstrated to be regulated by quorum sensing (QS). Plantain Herb has been used as antibacterial agents for many centuries in China. In this study, we analyzed Plantain Herb Extracts (PHE) at the concentration of 16 μg/mL (Group A, MIC), 8 μg/mL (Group B, 1/2 MIC) and 4 μg/mL (Group C, 1/4 MIC) for inhibition of the virulence factors production and biofilm formation in P. aeruginosa PAO1. The virulence factors included pyocyanin, rhamnolipids, protease and alginate. PHE showed significant inhibition of virulence factors as compared to the control group without interfering its growth. Thus, PHE might be a potent QS inhibitor and anti-biofilm agent in the treatment of Pseudomonas aeruginosa infections.

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

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.

scholarly journals Cladodionen Is a Potential Quorum Sensing Inhibitor Against Pseudomonas aeruginosa

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 205 ◽  
Author(s):  
Mengjia Wang ◽  
Lu Zhao ◽  
Hao Wu ◽  
Chaoyue Zhao ◽  
Qianhong Gong ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Binding Affinity ◽  
Virulence Factors ◽  
Jiaozhou Bay ◽  
Opportunistic Pathogen ◽  
Inhibitory Effect ◽  
Marine Fungus ◽  
Docking Analysis ◽  
Novel Approach

Pseudomonas aeruginosa is an opportunistic pathogen using virulence factors and biofilm regulated by quorum sensing (QS) systems to infect patients and protect itself from environmental stress and antibiotics. Interfering with QS systems is a novel approach to combat P. aeruginosa infections without killing the bacteria, meaning that it is much harder for bacteria to develop drug resistance. A marine fungus Cladosporium sp. Z148 with anti-QS activity was obtained from Jiaozhou Bay, China. Cladodionen, a novel QS inhibitor, was isolated from the extracts of this fungus. Cladodionen had a better inhibitory effect than pyocyanin on the production of elastase and rhamnolipid. It also inhibited biofilm formation and motilities. The mRNA expressions of QS-related genes, including receptor proteins (lasR, rhlR and pqsR), autoinducer synthases (lasI, rhlI and pqsA) and virulence factors (lasB and rhlA) were down-regulated by cladodionen. Molecular docking analysis showed that cladodionen had better binding affinity to LasR and PqsR than natural ligands. Moreover, the binding affinity of cladodionen to LasR was higher than to PqsR. Cladodionen exhibits potential as a QS inhibitor against P. aeruginosa, and its structure–activity relationships should be further studied to illustrate the mode of action, optimize its structure and improve anti-QS activity.

scholarly journals Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

2016 ◽  
Vol 12 ◽  
pp. 1428-1433 ◽  
Author(s):  
Bernardas Morkunas ◽  
Balint Gal ◽  
Warren R J D Galloway ◽  
James T Hodgkinson ◽  
Brett M Ibbeson ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Cell Signalling ◽  
Opportunistic Pathogen ◽  
Wild Type ◽  
Wide Range ◽  
Potential Applications ◽  
Therapeutic Context ◽  
Pyocyanin Production

Pyocyanin is a small molecule produced by Pseudomonas aeruginosa that plays a crucial role in the pathogenesis of infections by this notorious opportunistic pathogen. The inhibition of pyocyanin production has been identified as an attractive antivirulence strategy for the treatment of P. aeruginosa infections. Herein, we report the discovery of an inhibitor of pyocyanin production in cultures of wild-type P. aeruginosa which is based around a 4-alkylquinolin-2(1H)-one scaffold. To the best of our knowledge, this is the first reported example of pyocyanin inhibition by a compound based around this molecular framework. The compound may therefore be representative of a new structural sub-class of pyocyanin inhibitors, which could potentially be exploited in in a therapeutic context for the development of critically needed new antipseudomonal agents. In this context, the use of wild-type cells in this study is notable, since the data obtained are of direct relevance to native situations. The compound could also be of value in better elucidating the role of pyocyanin in P. aeruginosa infections. Evidence suggests that the active compound reduces the level of pyocyanin production by inhibiting the cell–cell signalling mechanism known as quorum sensing. This could have interesting implications; quorum sensing regulates a range of additional elements associated with the pathogenicity of P. aeruginosa and there is a wide range of other potential applications where the inhibition of quorum sensing is desirable.

scholarly journals The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1

Microbiology ◽  
2011 ◽  
Vol 157 (7) ◽  
pp. 2120-2132 ◽  
Author(s):  
Olivier M. Vandeputte ◽  
Martin Kiendrebeogo ◽  
Tsiry Rasamiravaka ◽  
Caroline Stévigny ◽  
Pierre Duez ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Pathogenic Bacteria ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Gene Products ◽  
Strain Pao1 ◽  
Preliminary Screening ◽  
Mutant Strains

Preliminary screening of the Malagasy plant Combretum albiflorum for compounds attenuating the production of quorum sensing (QS)-controlled virulence factors in bacteria led to the identification of active fractions containing flavonoids. In the present study, several flavonoids belonging to the flavone, flavanone, flavonol and chalcone structural groups were screened for their capacity to reduce the production of QS-controlled factors in the opportunistic pathogen Pseudomonas aeruginosa (strain PAO1). Flavanones (i.e. naringenin, eriodictyol and taxifolin) significantly reduced the production of pyocyanin and elastase in P. aeruginosa without affecting bacterial growth. Consistently, naringenin and taxifolin reduced the expression of several QS-controlled genes (i.e. lasI, lasR, rhlI, rhlR, lasA, lasB, phzA1 and rhlA) in P. aeruginosa PAO1. Naringenin also dramatically reduced the production of the acylhomoserine lactones N-(3-oxododecanoyl)-l-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl-l-homoserine lactone (C4-HSL), which is driven by the lasI and rhlI gene products, respectively. In addition, using mutant strains deficient for autoinduction (ΔlasI and ΔrhlI) and LasR- and RhlR-based biosensors, it was shown that QS inhibition by naringenin not only is the consequence of a reduced production of autoinduction compounds but also results from a defect in the proper functioning of the RlhR–C4-HSL complex. Widely distributed in the plant kingdom, flavonoids are known for their numerous and determinant roles in plant physiology, plant development and in the success of plant–rhizobia interactions, but, as shown here, some of them also have a role as inhibitors of the virulence of pathogenic bacteria by interfering with QS mechanisms.

scholarly journals Roles of Two-Component Systems in Pseudomonas aeruginosa Virulence

2021 ◽  
Vol 22 (22) ◽  
pp. 12152
Author(s):  
Maria Sultan ◽  
Rekha Arya ◽  
Kyeong Kyu Kim
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Opportunistic Pathogen ◽  
Secretion Systems ◽  
Chronic Infections ◽  
Potential Threat ◽  
Wide Range ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

Pseudomonas aeruginosa is an opportunistic pathogen that synthesizes and secretes a wide range of virulence factors. P. aeruginosa poses a potential threat to human health worldwide due to its omnipresent nature, robust host accumulation, high virulence, and significant resistance to multiple antibiotics. The pathogenicity of P. aeruginosa, which is associated with acute and chronic infections, is linked with multiple virulence factors and associated secretion systems, such as the ability to form and utilize a biofilm, pili, flagella, alginate, pyocyanin, proteases, and toxins. Two-component systems (TCSs) of P. aeruginosa perform an essential role in controlling virulence factors in response to internal and external stimuli. Therefore, understanding the mechanism of TCSs to perceive and respond to signals from the environment and control the production of virulence factors during infection is essential to understanding the diseases caused by P. aeruginosa infection and further develop new antibiotics to treat this pathogen. This review discusses the important virulence factors of P. aeruginosa and the understanding of their regulation through TCSs by focusing on biofilm, motility, pyocyanin, and cytotoxins.

scholarly journals Phloroglucinol-Gold and -Zinc Oxide Nanoparticles: Antibiofilm and Antivirulence Activities towards Pseudomonas aeruginosa PAO1

Marine Drugs ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. 601
Author(s):  
Fazlurrahman Khan ◽  
Min-Gyun Kang ◽  
Du-Min Jo ◽  
Pathum Chandika ◽  
Won-Kyo Jung ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Zinc Oxide ◽  
Virulence Factors ◽  
Antimicrobial Agents ◽  
Early Stage ◽  
Nanoparticle Synthesis ◽  
Synthesis Of Nanoparticles ◽  
Human Pathogenic Bacterium ◽  
Wide Range ◽  
Materials Used

With the advancement of nanotechnology, several nanoparticles have been synthesized as antimicrobial agents by utilizing biologically derived materials. In most cases, the materials used for the synthesis of nanoparticles from natural sources are extracts. Natural extracts contain a wide range of bioactive components, making it difficult to pinpoint the exact component responsible for nanoparticle synthesis. Furthermore, the bioactive component present in the extract changes according to numerous environmental factors. As a result, the current work intended to synthesize gold (AuNPs) and zinc oxide (ZnONPs) nanoparticles using pure phloroglucinol (PG). The synthesized PG-AuNPs and PG-ZnONPs were characterized using a UV–Vis absorption spectrophotometer, FTIR, DLS, FE-TEM, zeta potential, EDS, and energy-dispersive X-ray diffraction. The characterized PG-AuNPs and PG-ZnONPs have been employed to combat the pathogenesis of Pseudomonas aeruginosa. P. aeruginosa is recognized as one of the most prevalent pathogens responsible for the common cause of nosocomial infection in humans. Antimicrobial resistance in P. aeruginosa has been linked to the development of recalcitrant phenotypic characteristics, such as biofilm, which has been identified as one of the major obstacles to antimicrobial therapy. Furthermore, P. aeruginosa generates various virulence factors that are a major cause of chronic infection. These PG-AuNPs and PG-ZnONPs significantly inhibit early stage biofilm and eradicate mature biofilm. Furthermore, these NPs reduce P. aeruginosa virulence factors such as pyoverdine, pyocyanin, protease, rhamnolipid, and hemolytic capabilities. In addition, these NPs significantly reduce P. aeruginosa swarming, swimming, and twitching motility. PG-AuNPs and PG-ZnONPs can be used as control agents for infections caused by the biofilm-forming human pathogenic bacterium P. aeruginosa.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
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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