Lemon Oils Attenuate the Pathogenicity of Pseudomonas aeruginosa by Quorum Sensing Inhibition.
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ABSTRACT:
SUBMITTER: Luciardi MC
PROVIDER: S-EPMC8151035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Pseudomonas aeruginosa las (lasR-lasI) and rhl (rhlR-rhlI) quorum-sensing systems regulate the expression of several virulence factors, including elastase and rhamnolipid. P. aeruginosa strain PR1-E4 is a lasR deletion mutant that contains a second, undefined mutation which allows production of elastase and rhamnolipid despite a nonfunctional las system. We have previously shown that this strain accomplishes this by increasing the expression of the autoinducer synthase gene rhlI. In this report, we show that the elastolytic phenotype of mutant PR1-E4 can be complemented with a P. aeruginosa homologue of the Escherichia coli dnaK mutation suppressor gene dksA. When supplied in trans on a multicopy plasmid, this gene completely suppressed elastase production by mutant PR1-E4. Cloning and Northern blot analysis revealed that dksA was neither mutated nor less transcribed in mutant PR1-E4. When overexpressed, dksA also reduced rhamnolipid production by both mutant PR1-E4 and the wild type, PAO1. Using Northern blot analysis and lacZ reporter fusions, we show that dksA inhibits rhlI, rhlAB, and lasB transcription. Exogenous N-butyryl-L-homoserine lactone overcame the reduced expression of rhlI and restored rhlAB and lasB expression, as well as elastase production. Our results suggest that the overproduction of the P. aeruginosa DksA homologue inhibits quorum-sensing-dependent virulence factor production by downregulating the transcription of the autoinducer synthase gene rhlI.
| S-EPMC95037 | biostudies-literature
Project description:Green tea, a water extract of non-fermented leaves of Camellia sinensis L., is one of the nonalcoholic beverages in China. It is becoming increasingly popular worldwide, because of its refreshing, mild stimulant and medicinal properties. Here we examined the quorum sensing inhibitory potentials of tea polyphenols (TP) as antivirulence compounds both in vitro and in vivo. Biosensor assay data suggested minimum inhibitory concentrations (MICs) of TP against selected pathogens were 6.25 ~ 12.5 mg/mL. At sub-MIC, TP can specifically inhibit the production of violacein in Chromobacterium violaceum 12472 with almost 98% reduction at 3.125 mg/mL without affecting its growth rate. Moreover, TP exhibited inhibitory effects on virulence phenotypes regulated by QS in Pseudomonas aeruginosa. The total proteolytic activity, elastase, swarming motility and biofilm formation were reduced in a concentration-dependent manner. In vivo, TP treatment resulted in the reduction of P. aeruginosa pathogenicity in Caenorhabditis elegans. When its concentration was 3.125 mg/mL, the survival rate reached 63.3%. In the excision wound infection model, the wound contraction percentage in treatment groups was relatively increased and the colony-forming units (CFU) in the wound area were significantly decreased. These results suggested that TP could be developed as a novel non-antibiotic QS inhibitor without killing the bacteria but as an antivirulence compound to control bacterial infection.
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Project description:With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed.
| S-EPMC2865528 | biostudies-literature
Project description:Clinically significant pathogens such as Pseudomonas aeruginosa evade the effects of antibiotics using quorum sensing (QS) systems, making antimicrobial resistance (AMR) a persistent and potentially fatal global health issue. Hence, QS has been identified as a novel therapeutic target for identifying novel drug candidates against P. aeruginosa, and plant-derived products, including essential oils, have been demonstrated as effective QS modulators. This study assessed the antipathogenic efficacy of essential oils from two sunflower cultivars (AGSUN 5102 CLP and AGSUN 5106 CLP) against P. aeruginosa ATCC 27853 in vitro and in silico. At the sub-inhibitory concentrations, both AGSUN 5102 CLP (62.61%) and AGSUN 5106 CLP (59.23%) competed favorably with cinnamaldehyde (60.74%) and azithromycin (65.15%) in suppressing the expression of QS-controlled virulence phenotypes and biofilm formation in P. aeruginosa. A further probe into the mechanism of anti-QS action of the oils over a 100-ns simulation period against Las QS system revealed that phylloquinone (-66.42 ± 4.63 kcal/mol), linoleic acid (-53.14 ± 3.53 kcal/mol), and oleic acid (-52.02 ± 3.91 kcal/mol) had the best affinity and structural compactness as potential modulators of LasR compared to cinnamaldehyde (-16.95 ± 1.75 kcal/mol) and azithromycin (-32.08 ± 10.54 kcal/mol). These results suggest that the identified compounds, especially phylloquinone, could be a possible LasR modulator and may represent a novel therapeutic alternative against infections caused by P. aeruginosa. As a result, phylloquinone could be further studied as a QS modulator and perhaps find utility in developing new therapeutics.
| S-EPMC10044302 | biostudies-literature
Project description:Pseudomonas aeruginosa is an important opportunistic pathogen, and the emergence of drug resistance greatly increased the difficulty of treating its infection. Cell density-dependent quorum sensing (QS) system not only regulates the virulence but also associates with the drug resistance of P. aeruginosa. Screening for agents targeting QS to inhibit bacterial virulence and pathogenicity is considered a promising strategy to combat P. aeruginosa infection. In the present study, sennoside A was found to be able to inhibit the QS expression of P. aeruginosa at subinhibitory concentrations. The QS-regulated virulence factors, including protease, elastase, rhamnolipid, and pyocyanin, were also inhibited by sennoside A at both transcriptional and translational levels. Moreover, sennoside A could suppress the motility of twitching, swimming, and swarming as well as the biofilm formation, which is associated with the acute and chronic infections of P. aeruginosa in a dose-dependent manner. The attenuated pathogenicity of P. aeruginosa by sennoside A was further verified by Chinese cabbage, Drosophila melanogaster, and Caenorhabditis elegans infection analysis. Further study found that sennoside A might target the las system, mainly LasR, to interfere with QS. All the results indicate that sennoside A could inhibit the QS system to attenuate its regulated virulence and pathogenicity via mainly targeting LasR in P. aeruginosa and further research to identify its anti-QS activity for other Gram-negative bacteria is warranted.
| S-EPMC9668863 | biostudies-literature
Project description:Antipathogenic drugs are a potential source of therapeutics, particularly following the emergence of multiple drug-resistant pathogenic microorganisms in the last decade. The inhibition of quorum sensing (QS) is an advanced antipathogenic approach for suppression of bacterial virulence and dissemination. This study aimed to investigate the inhibitory effect of some Egyptian medicinal plants on the QS signaling system of Pseudomonas aeruginosa. Among the tested plants, Mangifera indica exhibited the highest quorum sensing inhibition (QSI) activity against Chromobacterium violaceum ATCC 12472. Four pure compounds were extracted and identified; of these, methyl gallate (MG) showed the most potent QSI. MG had a minimum inhibitory concentration (MIC) of 512 g/mL against P. aeruginosa strains PAO1, PA14, Pa21, Pa22, Pa23, Pa24, and PAO-JP2. The virulence factors of PAO1, PA14, Pa21, Pa22, Pa23, and Pa24 were significantly inhibited by MG at 1/4 and 1/2 sub-MICs without affecting bacterial viability. Computational insights were performed by docking the MG compound on the LasR receptor, and the QSI behavior of MG was found to be mediated by three hydrogen bonds: Trp60, Arg61, and Thr75. This study indicates the importance of M. indica and MG in the inhibition and modulation of QS and QS-related virulence factors in P. aeruginosa.
| S-EPMC10589227 | biostudies-literature
Project description:In a process termed quorum sensing, bacteria use diffusible chemical signals to coordinate cell density-dependent gene expression. In the human pathogen Pseudomonas aeruginosa, quorum sensing controls hundreds of genes, many of which encode extracellular virulence factors. Quorum sensing is required for P. aeruginosa virulence in animal models. Curiously, quorum sensing-deficient variants, most of which carry a mutation in the gene encoding the central quorum sensing regulator lasR, are frequently isolated from acute and chronic infections. The mechanism for their emergence is not known. Here we provide experimental evidence suggesting that these lasR mutants are social cheaters that cease production of quorum-controlled factors and take advantage of their production by the group. We detected an emerging subpopulation of lasR mutants after approximately 100 generations of in vitro evolution of the P. aeruginosa wild-type strain under culture conditions that require quorum sensing for growth. Under such conditions, quorum sensing appears to impose a metabolic burden on the proliferating bacterial cell, because quorum-controlled genes not normally induced until cessation of growth were highly expressed early in growth, and a defined lasR mutant showed a growth advantage when cocultured with the parent strain. The emergence of quorum-sensing-deficient variants in certain environments is therefore an indicator of high quorum sensing activity of the bacterial population as a whole. It does not necessarily indicate that quorum sensing is insignificant, as has previously been suggested. Thus, novel antivirulence strategies aimed at disrupting bacterial communication may be particularly effective in such clinical settings.
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Project description:Pseudomonas aeruginosa, an important opportunistic pathogen, is capable of producing various virulence factors and forming biofilm that are regulated by quorum sensing (QS). It is known that targeting virulence factor production and biofilm formation instead of exerting selective pressure on growth such as conventional antibiotics can reduce multidrug resistance in bacteria. Therefore, many quorum-sensing inhibitors (QSIs) have been developed to prevent or treat this bacterial infection. In this study, wogonin, as an active ingredient from Agrimonia pilosa, was found to be able to inhibit QS system of P. aeruginosa PAO1. Wogonin downregulated the expression of QS-related genes and reduced the production of many virulence factors, such as elastase, pyocyanin, and proteolytic enzyme. In addition, wogonin decreased the extracellular polysaccharide synthesis and inhibited twitching, swimming, and swarming motilities and biofilm formation. The attenuation of pathogenicity in P. aeruginosa PAO1 by wogonin application was further validated in vivo by cabbage infection and fruit fly and nematode survival experiments. Further molecular docking analysis, pathogenicity examination of various QS-related mutants, and PQS signal molecule detection revealed that wogonin could interfere with PQS signal molecular synthesis by affecting pqsA and pqsR. Taken together, the results indicated that wogonin might be used as an anti-QS candidate drug to attenuate the infection caused by P. aeruginosa.
| S-EPMC8657757 | biostudies-literature
Project description:Pseudomonas aeruginosa is a well-known pathogenic bacterium that forms biofilms and produces virulence factors via quorum sensing (QS). Interfering with normal QS interactions between signal molecules and their cognate receptors is a developing strategy for attenuating its virulence. Here we tested the hypothesis that 6-gingerol, a pungent oil of fresh ginger, reduces biofilm formation and virulence by antagonistically binding to P. aeruginosa QS receptors. In silico studies demonstrated molecular binding occurs between 6-gingerol and the QS receptor LasR through hydrogen bonding and hydrophobic interactions. Experimentally 6-gingerol reduced biofilm formation, several virulence factors (e.g., exoprotease, rhamnolipid, and pyocyanin), and mice mortality. Further transcriptome analyses demonstrated that 6-gingerol successfully repressed QS-induced genes, specifically those related to the production of virulence factors. These results strongly support our hypothesis and offer insight into the molecular mechanism that caused QS gene repression.
| S-EPMC4345325 | biostudies-literature
Project description:In Pseudomonas aeruginosa quorum sensing (QS) activates the production of virulence factors, playing a critical role in pathogenesis. Multiple negative regulators modulate the timing and the extent of the QS response either in the pre-quorum or post-quorum phases of growth. This regulation likely increases P. aeruginosa phenotypic plasticity and population fitness, facilitating colonization of challenging environments such as higher organisms. Accordingly, in addition to the factors required for QS signals synthesis and response, also QS regulators have been proposed as targets for anti-virulence therapies. However, while it is known that P. aeruginosa mutants impaired in QS are attenuated in their pathogenic potential, the effect of mutations causing a dysregulated timing and/or magnitude of the QS response has been poorly investigated so far in animal models of infection. In order to investigate the impact of QS dysregulation on P. aeruginosa pathogenesis in a murine model of lung infection, the QteE and RsaL proteins have been selected as representatives of negative regulators controlling P. aeruginosa QS in the pre- and post-quorum periods, respectively. Results showed that the qteE mutation does not affect P. aeruginosa lethality and ability to establish chronic infection in mice, despite causing a premature QS response and enhanced virulence factors production in test tube cultures compared to the wild type. Conversely, the post-quorum dysregulation caused by the rsaL mutation hampers the establishment of P. aeruginosa chronic lung infection in mice without affecting the mortality rate. On the whole, this study contributes to a better understanding of the impact of QS regulation on P. aeruginosa phenotypic plasticity during the infection process. Possible fallouts of these findings in the anti-virulence therapy field are also discussed.
| S-EPMC4242533 | biostudies-literature