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

2012 ◽  
Vol 78 (7) ◽  
pp. 2410-2421 ◽  
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.

scholarly journals Disruption of Quorum Sensing and Virulence inBurkholderia cenocepaciaby a Structural Analogue of thecis-2-Dodecenoic Acid Signal

2019 ◽  
Vol 85 (8) ◽  
Author(s):  
Chaoyu Cui ◽  
Shihao Song ◽  
Chunxi Yang ◽  
Xiuyun Sun ◽  
Yutong Huang ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Bacterial Infections ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Burkholderia Cenocepacia ◽  
Enoic Acid ◽  
Acyl Homoserine Lactone ◽  
Structural Analogue ◽  
Content Type ◽  
Signal Production

ABSTRACTQuorum sensing (QS) signals are widely used by bacterial pathogens to control biological functions and virulence in response to changes in cell population densities.Burkholderia cenocepaciaemploys a molecular mechanism in which thecis-2-dodecenoic acid (namedBurkholderiadiffusiblesignalfactor [BDSF]) QS system regulatesN-acyl homoserine lactone (AHL) signal production and virulence by modulating intracellular levels of cyclic diguanosine monophosphate (c-di-GMP). Thus, inhibition of BDSF signaling may offer a non-antibiotic-based therapeutic strategy against BDSF-regulated bacterial infections. In this study, we report the synthesis of small-molecule mimics of the BDSF signal and evaluate their ability to inhibit BDSF QS signaling inB. cenocepacia. A novel structural analogue of BDSF, 14-Me-C16:Δ2(cis-14-methylpentadec-2-enoic acid), was observed to inhibit BDSF production and impair BDSF-regulated phenotypes inB. cenocepacia, including motility, biofilm formation, and virulence, while it did not inhibit the growth rate of this pathogen. 14-Me-C16:Δ2also reduced AHL signal production. Genetic and biochemical analyses showed that 14-Me-C16:Δ2inhibited the production of the BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Notably, 14-Me-C16:Δ2attenuated BDSF-regulated phenotypes in variousBurkholderiaspecies. These findings suggest that 14-Me-C16:Δ2could potentially be developed as a new therapeutic agent against pathogenicBurkholderiaspecies by interfering with their QS signaling.IMPORTANCEBurkholderia cenocepaciais an important opportunistic pathogen which can cause life-threatening infections in susceptible individuals, particularly in cystic fibrosis and immunocompromised patients. It usually employs two types of quorum sensing (QS) systems, including thecis-2-dodecenoic acid (BDSF) system andN-acyl homoserine lactone (AHL) system, to regulate virulence. In this study, we have designed and identified an unsaturated fatty acid compound (cis-14-methylpentadec-2-enoic acid [14-Me-C16:Δ2]) that is capable of interfering withB. cenocepaciaQS signaling and virulence. We demonstrate that 14-Me-C16:Δ2reduced BDSF and AHL signal production inB. cenocepacia. It also impaired QS-regulated phenotypes in variousBurkholderiaspecies. These results suggest that 14-Me-C16:Δ2could interfere with QS signaling in manyBurkholderiaspecies and might be developed as a new antibacterial agent.

scholarly journals Evolution of Pseudomonas aeruginosa Virulence as a Result of Phage Predation

2013 ◽  
Vol 79 (19) ◽  
pp. 6110-6116 ◽  
Author(s):  
Zeinab Hosseinidoust ◽  
Theo G. M. van de Ven ◽  
Nathalie Tufenkji
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mammalian Cells ◽  
Bacterial Infections ◽  
Membrane Damage ◽  
Human Keratinocytes ◽  
Host Population ◽  
Resistant Bacteria ◽  
Content Type ◽  
Metabolic Action

ABSTRACTThe rapid increase in the emergence of antibiotic-resistant bacteria has attracted attention to bacteriophages for treating and preventing bacterial infections. Bacteriophages can drive the diversification ofPseudomonas aeruginosa, giving rise to phage-resistant variants with different phenotypes from their ancestral hosts. In this study, we sought to investigate the effect of phage resistance on cytotoxicity of host populations toward cultured mammalian cells. The library of phage-resistantP. aeruginosaPAO1 variants used was developed previously via experimental evolution of an isogenic host population using phages PP7 and E79. Our results presented herein indicate that the phage-resistant variants developed in a heterogeneous phage environment exhibit a greater ability to impede metabolic action of cultured human keratinocytes and have a greater tendency to cause membrane damage even though they cannot invade the cells in large numbers. They also show a heightened resistance to phagocytosis by model murine macrophages. Furthermore, all isolates produced higher levels of at least one of the secreted virulence factors, namely, total proteases, elastase, phospholipase C, and hemolysins. Reverse transcription-quantitative PCR (RT-qPCR) revealed upregulation in the transcription of a number of genes associated with virulence ofP. aeruginosafor the phage-resistant variants. The results of this study indicate a significant change in thein vitrovirulence ofP. aeruginosafollowing phage predation and highlight the need for caution in the selection and design of phages and phage cocktails for therapeutic use.

scholarly journals Identification of FDA-Approved Drugs as Antivirulence Agents Targeting the pqs Quorum-Sensing System of Pseudomonas aeruginosa

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Francesca D'Angelo ◽  
Valerio Baldelli ◽  
Nigel Halliday ◽  
Paolo Pantalone ◽  
Fabio Polticelli ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Antifungal Drugs ◽  
Phenotypic Characterization ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Active Inhibitor ◽  
Content Type ◽  
Approved Drugs

ABSTRACT The long-term use of antibiotics has led to the emergence of multidrug-resistant bacteria. A promising strategy to combat bacterial infections aims at hampering their adaptability to the host environment without affecting growth. In this context, the intercellular communication system quorum sensing (QS), which controls virulence factor production and biofilm formation in diverse human pathogens, is considered an ideal target. Here, we describe the identification of new inhibitors of the pqs QS system of the human pathogen Pseudomonas aeruginosa by screening a library of 1,600 U.S. Food and Drug Administration-approved drugs. Phenotypic characterization of ad hoc engineered strains and in silico molecular docking demonstrated that the antifungal drugs clotrimazole and miconazole, as well as an antibacterial compound active against Gram-positive pathogens, clofoctol, inhibit the pqs system, probably by targeting the transcriptional regulator PqsR. The most active inhibitor, clofoctol, specifically inhibited the expression of pqs-controlled virulence traits in P. aeruginosa, such as pyocyanin production, swarming motility, biofilm formation, and expression of genes involved in siderophore production. Moreover, clofoctol protected Galleria mellonella larvae from P. aeruginosa infection and inhibited the pqs QS system in P. aeruginosa isolates from cystic fibrosis patients. Notably, clofoctol is already approved for clinical treatment of pulmonary infections caused by Gram-positive bacterial pathogens; hence, this drug has considerable clinical potential as an antivirulence agent for the treatment of P. aeruginosa lung infections.

scholarly journals The Concerted Action of Two B3-Like Prophage Genes Excludes Superinfecting Bacteriophages by Blocking DNA Entry into Pseudomonas aeruginosa

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Marco Antonio Carballo-Ontiveros ◽  
Adrián Cazares ◽  
Pablo Vinuesa ◽  
Luis Kameyama ◽  
Gabriel Guarneros
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Pathogenic Bacteria ◽  
Phage Therapy ◽  
Alternative Therapy ◽  
Multidrug Resistant ◽  
Open Reading Frames ◽  
Resistant Bacteria ◽  
Content Type ◽  
Secondary Infections ◽  
Genes Encoding

ABSTRACT In this study, we describe seven vegetative phage genomes homologous to the historic phage B3 that infect Pseudomonas aeruginosa. Like other phage groups, the B3-like group contains conserved (core) and variable (accessory) open reading frames (ORFs) grouped at fixed regions in their genomes; however, in either case, many ORFs remain without assigned functions. We constructed lysogens of the seven B3-like phages in strain Ps33 of P. aeruginosa, a novel clinical isolate, and assayed the exclusion phenotype against a variety of temperate and virulent superinfecting phages. In addition to the classic exclusion conferred by the phage immunity repressor, the phenotype observed in B3-like lysogens suggested the presence of other exclusion genes. We set out to identify the genes responsible for this exclusion phenotype. Phage Ps56 was chosen as the study subject since it excluded numerous temperate and virulent phages. Restriction of the Ps56 genome, cloning of several fragments, and resection of the fragments that retained the exclusion phenotype allowed us to identify two core ORFs, so far without any assigned function, as responsible for a type of exclusion. Neither gene expressed separately from plasmids showed activity, but the concurrent expression of both ORFs is needed for exclusion. Our data suggest that phage adsorption occurs but that phage genome translocation to the host’s cytoplasm is defective. To our knowledge, this is the first report on this type of exclusion mediated by a prophage in P. aeruginosa. IMPORTANCE Pseudomonas aeruginosa is a Gram-negative bacterium frequently isolated from infected immunocompromised patients, and the strains are resistant to a broad spectrum of antibiotics. Recently, the use of phages has been proposed as an alternative therapy against multidrug-resistant bacteria. However, this approach may present various hurdles. This work addresses the problem that pathogenic bacteria may be lysogenized by phages carrying genes encoding resistance against secondary infections, such as those used in phage therapy. Discovering phage genes that exclude superinfecting phages not only assigns novel functions to orphan genes in databases but also provides insight into selection of the proper phages for use in phage therapy.

scholarly journals Synergistic Efficacy of Aedes aegypti Antimicrobial Peptide Cecropin A2 and Tetracycline against Pseudomonas aeruginosa

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Zhaojun Zheng ◽  
Nagendran Tharmalingam ◽  
Qingzhong Liu ◽  
Elamparithi Jayamani ◽  
Wooseong Kim ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Aedes Aegypti ◽  
Mammalian Cells ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Synergistic Activity ◽  
Content Type

ABSTRACT The increasing prevalence of antibiotic resistance has created an urgent need for alternative drugs with new mechanisms of action. Antimicrobial peptides (AMPs) are promising candidates that could address the spread of multidrug-resistant bacteria, either alone or in combination with conventional antibiotics. We studied the antimicrobial efficacy and bactericidal mechanism of cecropin A2, a 36-residue α-helical cationic peptide derived from Aedes aegypti cecropin A, focusing on the common pathogen Pseudomonas aeruginosa. The peptide showed little hemolytic activity and toxicity toward mammalian cells, and the MICs against most clinical P. aeruginosa isolates were 32 to 64 μg/ml, and its MICs versus other Gram-negative bacteria were 2 to 32 μg/ml. Importantly, cecropin A2 demonstrated synergistic activity against P. aeruginosa when combined with tetracycline, reducing the MICs of both agents by 8-fold. The combination was also effective in vivo in the P. aeruginosa/Galleria mellonella model (P < 0.001). We found that cecropin A2 bound to P. aeruginosa lipopolysaccharides, permeabilized the membrane, and interacted with the bacterial genomic DNA, thus facilitating the translocation of tetracycline into the cytoplasm. In summary, the combination of cecropin A2 and tetracycline demonstrated synergistic antibacterial activity against P. aeruginosa in vitro and in vivo, offering an alternative approach for the treatment of P. 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 Post-antibiotic era in hemodialysis? Two case reports of simultaneous colonization and bacteremia by multidrug-resistant bacteria

2020 ◽  
Author(s):  
Johanna M. Vanegas ◽  
Lorena Salazar-Ospina ◽  
Gustavo A. Roncancio ◽  
Julián Builes ◽  
Judy Natalia Jiménez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Case Reports ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Control Measures ◽  
Resistant Bacteria ◽  
Multidrug Resistant Bacteria ◽  
E Coli ◽  
Carbapenem Resistant

ABSTRACT The emergence of resistance mechanisms not only limits the therapeutic options for common bacterial infections but also worsens the prognosis in patients who have conditions that increase the risk of bacterial infections. Thus, the effectiveness of important medical advances that seek to improve the quality of life of patients with chronic diseases is threatened. We report the simultaneous colonization and bacteremia by multidrug-resistant bacteria in two hemodialysis patients. The first patient was colonized by carbapenem- and colistin-resistant Klebsiella pneumoniae, carbapenem-resistant Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). The patient had a bacteremia by MRSA, and molecular typing methods confirmed the colonizing isolate was the same strain that caused infection. The second case is of a patient colonized by extended-spectrum beta-lactamases (ESBL)-producing Escherichia coli and carbapenem-resistant Pseudomonas aeruginosa. During the follow-up period, the patient presented three episodes of bacteremia, one of these caused by ESBL-producing E. coli. Molecular methods confirmed colonization by the same clone of ESBL-producing E. coli at two time points, but with a different genetic pattern to the strain isolated from the blood culture. Colonization by multidrug-resistant bacteria allows not only the spread of these microorganisms, but also increases the subsequent risk of infections with limited treatments options. In addition to infection control measures, it is important to establish policies for the prudent use of antibiotics in dialysis units.

scholarly journals Conversion of the Pseudomonas aeruginosa Quinolone Signal and Related Alkylhydroxyquinolines by Rhodococcus sp. Strain BG43

2014 ◽  
Vol 80 (23) ◽  
pp. 7266-7274 ◽  
Author(s):  
Christine Müller ◽  
Franziska S. Birmes ◽  
Heiko Niewerth ◽  
Susanne Fetzner
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Rhodococcus Erythropolis ◽  
Opportunistic Pathogen ◽  
Biosynthetic Enzyme ◽  
Signal Molecule ◽  
Content Type ◽  
Cell Extracts ◽  
Specific Pathway ◽  
Rhodococcus Sp

ABSTRACTA bacterial strain, which based on the sequences of its 16S rRNA,gyrB,catA, andqsdAgenes, was identified as aRhodococcussp. closely related toRhodococcus erythropolis, was isolated from soil by enrichment on thePseudomonasquinolone signal [PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone], a quorum sensing signal employed by the opportunistic pathogenPseudomonas aeruginosa. The isolate, termedRhodococcussp. strain BG43, cometabolically degraded PQS and its biosynthetic precursor 2-heptyl-4(1H)-quinolone (HHQ) to anthranilic acid. HHQ degradation was accompanied by transient formation of PQS, and HHQ hydroxylation by cell extracts required NADH, indicating that strain BG43 has a HHQ monooxygenase isofunctional to the biosynthetic enzyme PqsH ofP. aeruginosa. The enzymes catalyzing HHQ hydroxylation and PQS degradation were inducible by PQS, suggesting a specific pathway. Remarkably,Rhodococcussp. BG43 is also capable of transforming 2-heptyl-4-hydroxyquinoline-N-oxide to PQS. It thus converts an antibacterial secondary metabolite ofP. aeruginosato a quorum sensing signal molecule.

scholarly journals Resistance Evolution against Phage Combinations Depends on the Timing and Order of Exposure

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Rosanna C. T. Wright ◽  
Ville-Petri Friman ◽  
Margaret C. M. Smith ◽  
Michael A. Brockhurst
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Multidrug Resistant ◽  
Fitness Costs ◽  
Evolutionary Trajectory ◽  
Promising Alternative ◽  
Content Type ◽  
Resistance Evolution

ABSTRACTPhage therapy is a promising alternative to chemotherapeutic antibiotics for the treatment of bacterial infections. However, despite recent clinical uses of combinations of phages to treat multidrug-resistant infections, a mechanistic understanding of how bacteria evolve resistance against multiple phages is lacking, limiting our ability to deploy phage combinations optimally. Here, we show, usingPseudomonas aeruginosaand pairs of phages targeting shared or distinct surface receptors, that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance. Whereas sequential exposure allowed bacteria to acquire multiple resistance mutations effective against both phages, this evolutionary trajectory was prevented by simultaneous exposure, resulting in quantitatively weaker resistance. The order of phage exposure determined the fitness costs of sequential resistance, such that certain sequential orders imposed much higher fitness costs than the same phage pair in the reverse order. Together, these data suggest that phage combinations can be optimized to limit the strength of evolved resistances while maximizing their associated fitness costs to promote the long-term efficacy of phage therapy.IMPORTANCEGlobally rising rates of antibiotic resistance have renewed interest in phage therapy where combinations of phages have been successfully used to treat multidrug-resistant infections. To optimize phage therapy, we first need to understand how bacteria evolve resistance against combinations of multiple phages. Here, we use simple laboratory experiments and genome sequencing to show that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance evolution in the opportunistic pathogenPseudomonas aeruginosa. These findings suggest that phage combinations can be optimized to limit the emergence and persistence of resistance, thereby promoting the long-term usefulness of phage therapy.

scholarly journals Combinatorial quorum sensing in Pseudomonas aeruginosa allows for novel cheating strategies

Microbiology ◽  
2020 ◽  
Vol 166 (8) ◽  
pp. 777-784 ◽  
Author(s):  
James Gurney ◽  
Sheyda Azimi ◽  
Sam P. Brown ◽  
Stephen P. Diggle
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Type Species ◽  
Natural Populations ◽  
Opportunistic Pathogen ◽  
Growth Media ◽  
Public And Private ◽  
Content Type ◽  
Private Goods ◽  
Link Type

In the opportunistic pathogen Pseudomonas aeruginosa, quorum sensing (QS) is a social trait that is exploitable by non-cooperating cheats. Previously it has been shown that by linking QS to the production of both public and private goods, cheats can be prevented from invading populations of cooperators and this was described by Dandekar et al. (Science 2012;338:264–266) as ‘a metabolic incentive to cooperate’. We hypothesized that P. aeruginosa could evolve novel cheating strategies to circumvent private goods metabolism by rewiring its combinatorial response to two QS signals (3O-C12-HSL and C4-HSL). We performed a selection experiment that cycled P. aeruginosa between public and private goods growth media and evolved an isolate that rewired its control of cooperative protease expression from a synergistic (AND-gate) response to dual-signal input to a 3O-C12-HSL-only response. We show that this isolate circumvents metabolic incentives to cooperate and acts as a combinatorial signalling cheat, with higher fitness in competition with its ancestor. Our results show three important principles: first, combinatorial QS allows for diverse social strategies to emerge; second, restrictions levied by private goods are not sufficient to explain the maintenance of cooperation in natural populations; and third, modifying combinatorial QS responses could result in important physiological outcomes in bacterial populations.

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