Quorum sensing inhibition of hordenine analogs on Pseudomonas aeruginosa and Serratia marcescens
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC8573111 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Quorum sensing is a regulatory system for controlling gene expression in response to increasing cell density. N-Acylhomoserine lactone (AHL) is produced by gram-negative bacteria, which use it as a quorum-sensing signal molecule. Serratia marcescens is a gram-negative opportunistic pathogen which is responsible for an increasing number of serious nosocomial infections. S. marcescens AS-1 produces N-hexanoyl homoserine lactone (C(6)-HSL) and N-(3-oxohexanoyl) homoserine lactone and regulates prodigiosin production, swarming motility, and biofilm formation by AHL-mediated quorum sensing. We synthesized a series of N-acyl cyclopentylamides with acyl chain lengths ranging from 4 to 12 and estimated their inhibitory effects on prodigiosin production in AS-1. One of these molecules, N-nonanoyl-cyclopentylamide (C(9)-CPA), had a strong inhibitory effect on prodigiosin production. C(9)-CPA also inhibited the swarming motility and biofilm formation of AS-1. A competition assay revealed that C(9)-CPA was able to inhibit quorum sensing at four times the concentration of exogenous C(6)-HSL and was more effective than the previously reported halogenated furanone. Our results demonstrated that C(9)-CPA was an effective quorum-sensing inhibitor for S. marcescens AS-1.
| S-EPMC2075062 | biostudies-literature
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:The focal intent of this study was to find out an alternative strategy for the antibiotic usage against bacterial infections. The quorum sensing inhibitory (QSI) activity of marine sponges collected from Palk Bay, India was evaluated against acyl homoserine lactone (AHL) mediated violacein production in Chromobacterium violaceum (ATCC 12472), CV026 and virulence gene expressions in clinical isolate Serratia marcescens PS1. Out of 29 marine sponges tested, the methanol extracts of Aphrocallistes bocagei (TS 8), Haliclona (Gellius) megastoma (TS 25) and Clathria atrasanguinea (TS 27) inhibited the AHL mediated violacein production in C. violaceum (ATCC 12472) and CV026. Further, these sponge extracts inhibited the AHL dependent prodigiosin pigment, virulence enzymes such as protease, hemolysin production and biofilm formation in S. marcescens PS1. However, these sponge extracts were not inhibitory to bacterial growth, which reveals the fact that the QSI activity of these extracts was not related to static or killing effects on bacteria. Based on the obtained results, it is envisaged that the marine sponges could pave the way to prevent quorum sensing (QS) mediated bacterial infections.
| S-EPMC3386442 | biostudies-literature
Project description:This study investigated the antivirulence capacity and mechanism of apple-skin-derived phloretin against Serratia marcescens NJ01, a vegetable spoilage bacterium. At 0.5 to 2 mg/mL doses, phloretin considerably inhibited the secretion of acyl homoserine lactones (AHLs), indicating that phloretin disrupted quorum sensing (QS) in S. marcescens NJ01. The dysfunction of QS resulted in reduced biofilms and the decreased production of protease, prodigiosin, extracellular polysaccharides (EPSs), and swimming and swarming motilities. Dysfunctional QS also weakened the activity of antioxidant enzymes and improved oxidative injury. The improved oxidative injury changed the composition of the membrane, improved membrane permeability, and eventually increased the susceptibility of biofilm cells to amikacin, netilmicin, and imipenem. The disrupted QS and enhanced oxidative stress also caused disorders of amino acid metabolism, energy metabolism, and nucleic acid metabolism, and ultimately attenuated the ability of S. marcescens NJ01 to induce spoilage. Our results indicated that phloretin can act as a potent drug to defend against spoilage by S. marcescens.
| S-EPMC10746122 | biostudies-literature
Project description:Serratia marcescens is an opportunistic pathogen and a major cause of ocular infections. In previous studies of S. marcescens MG1, we showed that biofilm maturation and sloughing were regulated by N-acyl homoserine lactone (AHL)-based quorum sensing (QS). Because of the importance of adhesion in initiating biofilm formation and infection, the primary goal of this study was to determine whether QS is important in adhesion to both abiotic and biotic surfaces, as assessed by determining the degree of attachment to hydrophilic tissue culture plates and human corneal epithelial (HCE) cells. Our results demonstrate that while adhesion to the abiotic surface was AHL regulated, adhesion to the HCE cell biotic surface was not. Type I fimbriae were identified as the critical adhesin for non-QS-mediated attachment to the biotic HCE cell surface but played no role in adhesion to the abiotic surface. While we were not able to identify a single QS-regulated adhesin essential for attachment to the abiotic surface, four AHL-regulated genes involved in adhesion to the abiotic surface were identified. Interestingly, two of these genes, bsmA and bsmB, were also shown to be involved in adhesion to the biotic surface in a non-QS-controlled fashion. Therefore, the expression of these two genes appears to be cocontrolled by regulators other than the QS system for mediation of attachment to HCE cells. We also found that QS in S. marcescens regulates other potential cell surface adhesins, including exopolysaccharide and the outer membrane protein OmpX. We concluded that S. marcescens MG1 utilizes different regulatory systems and adhesins in attachment to biotic and abiotic surfaces and that QS is a main regulatory pathway in adhesion to an abiotic surface but not in adhesion to a biotic surface.
| S-EPMC1855814 | biostudies-literature
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:Phosphate is an essential nutrient for heterotrophic bacteria, affecting bacterioplankton in aquatic ecosystems and bacteria in biofilms. However, the influence of phosphate limitation on bacterial competition and biofilm development in multispecies populations has received limited attention in existing studies. To address this issue, we isolated 13 adhesive bacteria from paper machine aggregates. Intergeneric inhibition of Pseudomonas aeruginosa WW5 by Serratia marcescens WW4 was identified under phosphate-limited conditions, but not in Luria-Bertani medium or M9 minimal medium. The viable numbers of the pure S. marcescens WW4 culture decreased over 3 days in the phosphate-limited medium; however, the mortality of S. marcescens WW4 was significantly reduced when it was co-cultured with P. aeruginosa WW5, which appeared to sustain the S. marcescens WW4 biofilm. In contrast, viable P. aeruginosa WW5 cells immediately declined in the phosphate-limited co-culture. To identify the genetic/inhibitory element(s) involved in this process, we inserted a mini-Tn5 mutant of S. marcescens WW4 that lacked inhibitory effect. The results showed that an endonuclease bacteriocin was involved in this intergeneric inhibition by S. marcescens WW4 under phosphate limitation. In conclusion, this study highlights the importance of nutrient limitation in bacterial interactions and provides a strong candidate gene for future functional characterisation.
| S-EPMC3717176 | biostudies-literature
Project description:Background and objectivesSerratia marcescens has emerged as a nosocomial pathogen responsible for human infections, where antibiotic resistance further complicates the treatments. In S. marcescens, biofilm formation and virulence factor production are controlled via quorum sensing (QS) system. QS is a signaling system that enables gene regulation to control diverse physiological functions in bacteria. Essential oils have shown to be potential in diminishing the pathogenicity and virulence of drug-resistant bacteria. This study was performed to determine whether eugenol would affect QS system, biofilm formation and virulence factor production of S. marcescens.Materials and methodsBiofilm formation, extracellular virulence factor production (hemolysin and protease), swarming motility and pigment formation of S. marcescens ATCC 13880 and S. marcescens Sm2 were assessed after eugenol exposure at 1.25 and 2.5 µg/ml concentrations. The expression of genes involved in motility (flhD), attachment (fimC), biofilm formation (bsmB, bsmA), and QS regulatory (swrR) were also evaluated.ResultsEugenol treatment at 1.25 and 2.5 µg/ml concentrations caused a significant reduction in biofilm formation. The pigment, hemolysin and protease production of two studied S. marcescens strains, also reduced significantly by eugenol treatments (p<0.05). The bsmA, bsmB, flhD and fimC genes were down-regulated after eugenol treatment. The swrR gene expression was also reduced significantly by eugenol in both S. marcescens strains (p<0.05).ConclusionEugenol inhibited quorum sensing-regulated functions of two studied S. marcescens strains.
| S-EPMC7867707 | biostudies-literature
Project description:The development of bacterial resistance is an increasing global concern that requires discovering new antibacterial agents and strategies. Bacterial quorum sensing (QS) systems play important roles in controlling bacterial virulence, and their targeting could lead to diminishing bacterial pathogenesis. In this context, targeting QS systems without significant influence on bacterial growth is assumed as a promising strategy to overcome resistance development. This study aimed at evaluating the anti-QS and anti-virulence activities of the β-adrenoreceptor antagonist propranolol at sub-minimal inhibitory concentrations (sub-MIC) against two Gram-negative bacterial models Pseudomonas aeruginosa and Serratia marcescens. The effect of propranolol on the expression of QS-encoding genes was evaluated. Additionally, the affinity of propranolol to QS receptors was virtually attested. The influence of propranolol at sub-MIC on biofilm formation, motility, and production of virulent factors was conducted. The outcomes of the propranolol combination with different antibiotics were assessed. Finally, the in vivo protection assay in mice was performed to assess propranolol's effect on lessening the bacterial pathogenesis. The current findings emphasized the significant ability of propranolol at sub-MIC to reduce the formation of biofilms, motility, and production of virulence factors. In addition, propranolol at sub-MIC decreased the capacity of tested bacteria to induce pathogenesis in mice. Furthermore, propranolol significantly downregulated the QS-encoding genes and showed significant affinity to QS receptors. Finally, propranolol at sub-MIC synergistically decreased the MICs of different antibiotics against tested bacteria. In conclusion, propranolol might serve as a plausible adjuvant therapy with antibiotics for the treatment of serious bacterial infections after further pharmacological and pharmaceutical studies.
| S-EPMC10741015 | 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