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PubMed2005

Membrane vesicles traffic signals and facilitate group activities in a prokaryote.

Many bacteria use extracellular signals to communicate and coordinate social activities, a process referred to as quorum sensing. Many quorum signals have significant hydrophobic character, and how these signals are trafficked between bacteria within a population is not understood. Here we show that the opportunistic human pathogen Pseudomonas aeruginosa packages the signalling molecule 2-heptyl-3-hydroxy-4-quinolone (pseudomonas quinolone signal; PQS) into membrane vesicles that serve to traffic this molecule within a population. Removal of these vesicles from the bacterial population halts cell-cell communication and inhibits PQS-controlled group behaviour. We also show that PQS actively mediates its own packaging and the packaging of other antimicrobial quinolines produced by P. aeruginosa into vesicles. These findings illustrate that a prokaryote possesses a signal trafficking system with features common to those used by higher organisms and outlines a novel mechanism for delivery of a signal critical for coordinating group behaviour in P. aeruginosa.

Biological Transport↗
PubMed2005

Construction and analysis of a Mannheimia haemolytica A1 luxS mutant.

Mannheimia haemolytica A1 is the causative agent of bovine pneumonic pasteurellosis, a major cause of sickness, death, and economic loss to the feedlot cattle industry. M. haemolytica A1 produces autoinducer-2 (AI-2) like molecules that are capable of inducing quorum sensing system 2 of Vibrio harveyi. This interspecies quorum sensing system has been shown to regulate the expression of virulence genes in several pathogenic bacteria. The protein central to the production of AI-2 is LuxS. To determine if quorum sensing is involved in the regulation of virulence genes in M. haemolytica A1, a luxS mutant was constructed by replacing luxS with a cat cassette. This mutant was verified by PCR analysis, Southern hybridization, as well as its inability to induce bioluminescence in the V. harveyi reporter strain. RT-PCR analysis showed there was no difference in leukotoxin (lktC) mRNA levels, however there were increased mRNA levels of putative virulence associated genes, transferrin binding protein B (tbpB), adhesin (ahs) and capsule biosynthesis (nmaA). Electron microscopy showed that the level of encapsulation in the mutant is higher than the parent. Additionally, the mutant was slightly more adherent to bovine tracheal cells than the parent. In vitro competition assays showed the mutant out-competed the parent under iron-restricted conditions. However, in a calf challenge, the parent was the dominant isolate recovered.

Animals↗
PubMed2005

Femtomolar transition state analogue inhibitors of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Escherichia coli.

Escherichia coli 5'-methylthioadenosine/S-adenosyl-homocysteine nucleosidase (MTAN) hydrolyzes its substrates to form adenine and 5-methylthioribose (MTR) or S-ribosylhomocysteine (SRH). 5'-Methylthioadenosine (MTA) is a by-product of polyamine synthesis and SRH is a precursor to the biosynthesis of one or more quorum sensing autoinducer molecules. MTAN is therefore involved in quorum sensing, recycling MTA from the polyamine pathway via adenine phosphoribosyltransferase and recycling MTR to methionine. Hydrolysis of MTA by E. coli MTAN involves a highly dissociative transition state with ribooxacarbenium ion character. Iminoribitol mimics of MTA at the transition state of MTAN were synthesized and tested as inhibitors. 5'-Methylthio-Immucillin-A (MT-ImmA) is a slow-onset tight-binding inhibitor giving a dissociation constant (K(i)(*)) of 77 pm. Substitution of the methylthio group with a p-Cl-phenylthio group gives a more powerful inhibitor with a dissociation constant of 2 pm. DADMe-Immucillins are better inhibitors of E. coli MTAN, since they are more closely related to the highly dissociative nature of the transition state. MT-DADMe-Immucillin-A binds with a K(i)(*) value of 2 pm. Replacing the 5'-methyl group with other hydrophobic groups gave 17 transition state analogue inhibitors with dissociation constants from 10(-12) to 10(-14) m. The most powerful inhibitor was 5'-p-Cl-phenylthio-DADMe-Immucillin-A (pClPhT-DADMe-ImmA) with a K(i)(*) value of 47 fm (47 x 10(-15) m). These are among the most powerful non-covalent inhibitors reported for any enzyme, binding 9-91 million times tighter than the MTA and SAH substrates, respectively. The inhibitory potential of these transition state analogue inhibitors supports a transition state structure closely resembling a fully dissociated ribooxacarbenium ion. Powerful inhibitors of MTAN are candidates to disrupt key bacterial pathways including methylation, polyamine synthesis, methionine salvage, and quorum sensing. The accompanying article reports crystal structures of MTAN with these analogues.

Deoxyadenosines↗
PubMed2000

migA, a quorum-responsive gene of Pseudomonas aeruginosa, is highly expressed in the cystic fibrosis lung environment and modifies low-molecular-mass lipopolysaccharide.

Pseudomonas aeruginosa is an opportunistic human pathogen which poses a major threat to patients with cystic fibrosis (CF). Excessive amounts of mucus present in the lungs of CF patients promotes the colonization of P. aeruginosa. The migA gene, encoding a putative glycosyltransferase, has been shown to be highly inducible by respiratory mucus derived from CF patients. In this study, it is further demonstrated by population transcript analysis that the migA gene is highly expressed in the CF lung environment. Deletion analysis of the migA promoter identified a las-box-like sequence commonly found in promoters that are responsive to quorum sensing regulation. Further analysis of migA expression in quorum-sensing-defective strains, as well as its expression in response to autoinducer molecules, demonstrated that migA is regulated by the RhlI/RhlR quorum sensing regulatory system. Functionally, as the MigA sequence homology data suggested, the migA gene indeed affects the structure of LPS in P. aeruginosa. Increased expression of the migA gene results in a loss of core-plus-one LPS, while having no obvious effect on the long-chain O-antigen-bearing LPS. Although the exact biological role of the core-plus-one LPS is not clear, these experimental results suggest that migA up-regulation in the CF lung environment is part of the adaptive response which confers on P. aeruginosa a survival advantage.

Bacterial Proteins↗
PubMed1999

Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa.

Numerous species of bacteria use an elegant regulatory mechanism known as quorum sensing to control the expression of specific genes in a cell-density dependent manner. In Gram-negative bacteria, quorum sensing systems function through a cell-to-cell signal molecule (autoinducer) that consists of a homoserine lactone with a fatty acid side chain. Such is the case in the opportunistic human pathogen Pseudomonas aeruginosa, which contains two quorum sensing systems (las and rhl) that operate via the autoinducers, N-(3-oxododecanoyl)-L-homoserine lactone and N-butyryl-L-homoserine lactone. The study of these signal molecules has shown that they bind to and activate transcriptional activator proteins that specifically induce numerous P. aeruginosa virulence genes. We report here that P. aeruginosa produces another signal molecule, 2-heptyl-3-hydroxy-4-quinolone, which has been designated as the Pseudomonas quinolone signal. It was found that this unique cell-to-cell signal controlled the expression of lasB, which encodes for the major virulence factor, LasB elastase. We also show that the synthesis and bioactivity of Pseudomonas quinolone signal were mediated by the P. aeruginosa las and rhl quorum sensing systems, respectively. The demonstration that 2-heptyl-3-hydroxy-4-quinolone can function as an intercellular signal sheds light on the role of secondary metabolites and shows that P. aeruginosa cell-to-cell signaling is not restricted to acyl-homoserine lactones.

Bacterial Proteins↗
PubMed2005

The Pseudomonas chlororaphis PCL1391 sigma regulator psrA represses the production of the antifungal metabolite phenazine-1-carboxamide.

The rhizobacterium Pseudomonas chlororaphis PCL1391 produces the antifungal metabolite phenazine-1-carboxamide (PCN), which is a crucial trait in its competition with the phytopathogenic fungus Fusarium oxysporum f. sp. radicis-lycopersici in the rhizosphere. The expression of the PCN biosynthetic gene cluster in PCL1391 is population density-dependent and is regulated by the quorum-sensing genes phzI and phzR via synthesis of the autoinducer N-hexanoyl-L-homoserine lactone (C6-HSL). Here, we describe the identification of an additional regulatory gene of PCN biosynthesis in PCL1391. A mutation in the psrA gene (Pseudomonas sigma regulator), the gene product of which is a member of the TetR/AcrR family of transcriptional regulators, resulted in increased production of autoinducer molecules and PCN. Expression studies showed that inactivation of psrA resulted in increased expression of the phzI and phzR genes and the phz biosynthetic operon and that introduction of functional copies of psrA represses the expression of these genes, resulting in reduced production of autoinducer signal and PCN. Surprisingly, inactivation of psrA in the phzI or phzR quorum-sensing mutants, which do not produce detectable amounts of PCN and autoinducers by themselves, restored PCN biosynthesis. This phenomenon was accompanied by the appearance of compounds with autoinducer activities migrating at the positions of C4-HSL and C6-HSL on C18 reverse phase-thin-layer chromatography. These observations indicate that PsrA also represses at least one silent, yet unidentified, quorum-sensing system or autoinducer biosynthetic pathway in PCL1391. The expression of psrA declines at the onset of the stationary phase at the same moment at which quorum-sensing (-regulated) genes are activated. In addition, expression studies in a psrA- and a multicopy psrA background showed that psrA is autoregulated. Multiple copies of psrA repress its own expression. Mutation of gacS, encoding the sensor kinase member of a two-component global regulatory system significantly reduced production of autoinducers and PCN. We show a novel link between global regulation and quorum sensing via the PsrA regulator.

Antifungal Agents↗
PubMed2003

Chemical communication among bacteria.

Cell-cell communication in bacteria is accomplished through the exchange of chemical signal molecules called autoinducers. This process, called quorum sensing, allows bacteria to monitor their environment for the presence of other bacteria and to respond to fluctuations in the number and/or species present by altering particular behaviors. Most quorum-sensing systems are species- or group-specific, which presumably prevents confusion in mixed-species environments. However, some quorum-sensing circuits control behaviors that involve interactions among bacterial species. These quorum-sensing circuits can involve both intra- and interspecies communication mechanisms. Finally, anti-quorumsensing strategies are present in both bacteria and eukaryotes, and these are apparently designed to combat bacteria that rely on cell-cell communication for the successful adaptation to particular niches.

Bacterial Physiological Phenomena↗
PubMed2004

Regulation system for protease production in Vibrio vulnificus.

Vibrio vulnificus is a causative agent of serious food-borne diseases in humans related to consumption of raw seafoods. This human pathogen secretes a metalloprotease (VVP) that evokes enhancement of the vascular permeability and disruption of the capillaries. Production of microbial proteases is generally induced at early stationary phase of its growth. This cell density dependent regulation of VVP production in V. vulnificus known to be the quorum-sensing. When V. vulnificus was cultivated in Luria-Bertani (LB) medium, accumulation of the autoinducer, the signal molecule operating the quorum-sensing system, was detected. Moreover, expression of the vvp gene encoding VVP was found to be closely related with expression of the luxS gene that encode the synthase of the autoinducer precursor (luxS). These findings may indicate VVP production is controlled by the quorum-sensing system in LB medium. Furthermore, this system functioned more effectively at 26 degrees C than at 37 degrees C. When incubated at 37 degrees C in human serum supplemented with ferric chloride, production of VVP and expression of vvp increased in proportion to the concentration of ferric ion; whereas, expression of luxS was not increased. This suggests that VVP production in human serum containing ferric ion may be regulated mainly by the system other than the quorum-sensing system.

Bacterial Proteins↗
PubMed2006

Identification of potential CepR regulated genes using a cep box motif-based search of the Burkholderia cenocepacia genome.

BACKGROUND: The Burkholderia cenocepacia CepIR quorum sensing system has been shown to positively and negatively regulate genes involved in siderophore production, protease expression, motility, biofilm formation and virulence. In this study, two approaches were used to identify genes regulated by the CepIR quorum sensing system. Transposon mutagenesis was used to create lacZ promoter fusions in a cepI mutant that were screened for differential expression in the presence of N-acylhomoserine lactones. A bioinformatics approach was used to screen the B. cenocepacia J2315 genome for CepR binding site motifs. RESULTS: Four positively regulated and two negatively regulated genes were identified by transposon mutagenesis including genes potentially involved in iron transport and virulence. The promoter regions of selected CepR regulated genes and site directed mutagenesis of the cepI promoter were used to predict a consensus cep box sequence for CepR binding. The first-generation consensus sequence for the cep box was used to identify putative cep boxes in the genome sequence. Eight potential CepR regulated genes were chosen and the expression of their promoters analyzed. Six of the eight were shown to be regulated by CepR. A second generation motif was created from the promoters of these six genes in combination with the promoters of cepI, zmpA, and two of the CepR regulated genes identified by transposon mutagenesis. A search of the B. cenocepacia J2315 genome with the new motif identified 55 cep boxes in 65 promoter regions that may be regulated by CepR. CONCLUSION: Using transposon mutagenesis and bioinformatics expression of twelve new genes have been determined to be regulated by the CepIR quorum sensing system. A cep box consensus sequence has been developed based on the predicted cep boxes of ten CepR regulated genes. This consensus cep box has led to the identification of over 50 new genes potentially regulated by the CepIR quorum sensing system.

4-Butyrolactone↗
PubMed2006

Biosensing systems for the detection of bacterial quorum signaling molecules.

Bacterial quorum sensing (QS) is a cell-to-cell communication phenomenon that allows bacteria to control the expression of certain specialized genes depending on their cell population size. Signaling molecules such N-acylhomoserine lactones (AHLs) mediate the communication, and their concentration reflects the bacterial population density. Quorum sensing regulates several processes including bacterial pathogenicity. We developed a method for the rapid, sensitive, and quantitative detection of AHLs in biological samples such as saliva and stools. The method is based on whole-cell sensing systems that employ QS regulatory systems as recognition elements and the luxCDABE gene cassette as a reporter. The method proved to be reproducible when applied to real samples and was able to detect low analyte concentrations down to 1 x 10(-9) M without requiring extensive sample preparation. We envision that this novel biosensing system could be employed in the diagnosis and management of various bacteria-related disorders, thus supporting the use of quorum sensing molecules as potential biomarkers of disease. Due to cost-effectiveness and high throughput, these biosensing systems could be successfully employed as a new tool for the screening of novel drugs that target quorum sensing mechanisms.

Bacteria↗
PubMed2003

The Pseudomonas aeruginosa autoinducer N-3-oxododecanoyl homoserine lactone accelerates apoptosis in macrophages and neutrophils.

Quorum-sensing systems are critical regulators of the expression of virulence factors of various organisms, including Pseudomonas aeruginosa. Las and Rhl are two major quorum-sensing components, and they are regulated by their corresponding autoinducers, N-3-oxododecanoyl homoserine lactone (3-oxo-C(12)-HSL) and N-butyryl-L-homoserine lactone (C(4)-HSL). Recent progress has demonstrated the potential of quorum-sensing molecules, especially 3-oxo-C(12)-HSL, for modulation of the host immune system. Here we show the specific ability of 3-oxo-C(12)-HSL to induce apoptosis in certain types of cells. When bone marrow-derived macrophages were incubated with synthetic 3-oxo-C(12)-HSL, but when they were incubated not C(4)-HSL, significant loss of viability was observed in a concentration (12 to 50 micro M)- and incubation time (1 to 24 h)-dependent manner. The cytotoxic activity of 3-oxo-C(12)-HSL was also observed in neutrophils and monocytic cell lines U-937 and P388D1 but not in epithelial cell lines CCL-185 and HEp-2. Cells treated with 3-oxo-C(12)-HSL revealed morphological alterations indicative of apoptosis. Acceleration of apoptosis in 3-oxo-C(12)-HSL-treated cells was confirmed by multiple criteria (caspases 3 and 8, histone-associated DNA fragments, phosphatidylserine expression). Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C(12)-HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C(12)-HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C(12)-HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C(12)-HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.

4-Butyrolactone↗
PubMed2006

Let LuxS speak up in AI-2 signaling.

Quorum sensing is a process of bacterial cell-cell communication that uses small diffusible molecules to coordinate diverse behaviors in response to population density. The only quorum-sensing system shared by Gram-positive and Gram-negative bacteria involves the production of autoinducer-2 (AI-2). The AI-2 synthase LuxS is widely distributed among the Bacteria, which suggests that AI-2 is a language for interspecies communication. However, LuxS is also an integral component of the activated methyl cycle in bacteria. LuxS-based quorum sensing has been intensively studied in the past decade, mostly in relation to the AI-2 molecule and the downstream effects of luxS knockouts; few studies have focused on the gene and protein activity itself. Ongoing attempts to dissect the metabolic and signaling roles of LuxS leave little doubt that unraveling the regulation of luxS expression and cellular LuxS activity is the key to understanding LuxS-based quorum sensing.

Amino Acid Motifs↗
PubMed1999

[Some aspects of virulence].

GLYCOPEPTIDE INTERACTION AND THE STAPHYLOCOCCI WALL: Glycopeptides induce modifications in the cell wall of staphylococci. This modification has been observed in VISA strains and could involve bacterial adherence to materials. QUORUM SENSING: Bacterial virulence in Gram-negative germs is closely related to quorum sensing, a system regulated by bacterial inoculum. The use of strains deficient in different steps of quorum sensing in a experimental rat model has been useful in better understanding the pathophysiological effects linked to this system of virulence.

Animals↗
PubMed2004

Cell-to-cell signaling in intestinal pathogens.

In the conventional view of prokaryotic life, bacteria live a unicellular existence, with responses to external stimuli limited to the detection of chemical and physical signals of environmental origin. This view of bacteriology is now recognized as overly simplistic, because bacteria communicate with each other through small "hormone-like" organic compounds referred to as autoinducers (Als). These bacterial cell-to-cell signaling systems were initially described as mechanisms through which bacteria regulate gene expression via cell density, and, therefore, they have been named quorum sensing. When the Als reach a threshold concentration, they interact with regulatory proteins, thereby driving bacterial gene expression. Bacterial intercellular communication provides a mechanism for the regulation of gene expression resulting in coordinated population behavior. The functions controlled by quorum sensing are varied and reflect the needs of a particular species of bacteria inhabiting a given niche. Quorum sensing-controlled processes include bioluminescence, virulence factor expression, biofilm development, and conjugation among others. Enteric pathogens use quorum sensing to regulate genes involved in virulence, such as motility, and type III secretion. Quorum sensing is utilized to sense the presence of the normal intestinal flora and to warrant successful colonization of the host.

Bacterial Proteins↗
PubMed1998

In vitro cellular toxicity predicts Pseudomonas aeruginosa virulence in lung infections.

The role of quorum sensing by Pseudomonas aeruginosa in producing cytotoxicity has not been fully investigated. Strains of P. aeruginosa have been characterized as having an invasive or a cytotoxic phenotype (S. M. J. Fleiszig et al., Infect. Immun. 65:579-586, 1997). We noted that the application of a large inoculum of the invasive strain 6294 caused cytotoxicity of cultured epithelial cells. To investigate this dose-related cytotoxicity, we compared the behavior of 6294 to that of another invasive strain, PAO1, and determined whether the cytotoxicity could be related to quorum sensing. Both invasive strains, 6294 and PAO1, appear to have quorum-sensing systems that were operative when large doses of bacteria were applied to cultured lung epithelial cells or instilled into the lungs of animals. Nonetheless, only 6294 was cytotoxic. Cytotoxicity induced by 6294 correlated with increased elastase production. These experiments suggest that there are multiple mechanisms for the induction of cytotoxicity, pathology, and mortality in vivo. However, in vivo cytotoxicity and mortality, but not pathology, could be predicted by quantitative in vitro cellular damage experiments utilizing a range of bacteria-to-cell ratios. It appears that quorum sensing may inversely correlate with virulence in that strains that produced PAI [N-(3-oxododecanoyl) homoserine lactone] also appeared to attract more polymorphonuclear leukocytes in vivo and were possibly eliminated more quickly. In addition, exoproduct production in bacteriological medium in vitro may differ significantly from exoproduct expression from infections in vivo or during cocultivation of bacteria with tissue culture cells.

4-Butyrolactone↗
PubMed2002

Pseudomonas aeruginosa virulence analyzed in a Dictyostelium discoideum host system.

Pseudomonas aeruginosa is an important opportunistic pathogen that produces a variety of cell-associated and secreted virulence factors. P. aeruginosa infections are difficult to treat effectively because of the rapid emergence of antibiotic-resistant strains. In this study, we analyzed whether the amoeba Dictyostelium discoideum can be used as a simple model system to analyze the virulence of P. aeruginosa strains. The virulent wild-type strain PAO1 was shown to inhibit growth of D. discoideum. Isogenic mutants deficient in the las quorum-sensing system were almost as inhibitory as the wild type, while rhl quorum-sensing mutants permitted growth of Dictyostelium cells. Therefore, in this model system, factors controlled by the rhl quorum-sensing system were found to play a central role. Among these, rhamnolipids secreted by the wild-type strain PAO1 could induce fast lysis of D. discoideum cells. By using this simple model system, we predicted that certain antibiotic-resistant mutants of P. aeruginosa should show reduced virulence. This result was confirmed in a rat model of acute pneumonia. Thus, D. discoideum could be used as a simple nonmammalian host system to assess pathogenicity of P. aeruginosa.

Animals↗
PubMed2003

Fibrinogen depletion attenuates Staphyloccocus aureus infection by preventing density-dependent virulence gene up-regulation.

Staphylococcus aureus undergoes a density-dependent conversion in phenotype from tissue-adhering to tissue-damaging and phagocyte-evading that is mediated in part by the quorum-sensing operon, agr, and its effector, RNAIII. Contributions of host factors to this mechanism for regulating virulence have not been studied. We hypothesized that fibrinogen, as a component of the inflammatory response, could create spatially constrained microenvironments around bacteria that increase density independently of bacterial numbers and thus potentiate quorum-sensing-dependent virulence gene expression. Here we show that transient fibrinogen depletion significantly reduces the bacterial burden and the consequential morbidity and mortality during experimental infection with wild-type S. aureus, but not with bacteria that lack expression of the quorum-sensing operon, agr. In addition, it inhibits in vivo activation of the promoter for the agr effector, RNAIII, and downstream targets of RNAIII, including alpha hemolysin and capsule production. Moreover, both in vitro and in vivo, the mechanism for promoting this phenotypic switch in virulence involves clumping of the bacteria, demonstrating that S. aureus responds to fibrinogen-mediated bacterial clumping by enhancing density-dependent virulence gene expression. These data demonstrate that down-modulation of specific inflammatory components of the host that augment bacterial quorum sensing can be a strategy for enhancing host defense against infection.

Afibrinogenemia↗
PubMed2005

Three-dimensional structure of the quorum-quenching N-acyl homoserine lactone hydrolase from Bacillus thuringiensis.

The three-dimensional structure of the N-acyl-l-homoserine lactone hydrolase (AHL lactonase) from Bacillus thuringiensis has been determined, by using single-wavelength anomalous dispersion (SAD) phasing, to 1.6-angstroms resolution. AHLs are produced by many Gram-negative bacteria as signaling molecules used in quorum-sensing pathways that indirectly sense cell density and regulate communal behavior. Because of their importance in pathogenicity, quorum-sensing pathways have been suggested as potential targets for the development of novel therapeutics. Quorum-sensing can be disrupted by enzymes evolved to degrade these lactones, such as AHL lactonases. These enzymes are members of the metallo-beta-lactamase superfamily and contain two zinc ions in their active sites. The zinc ions are coordinated to a number of ligands, including a single oxygen of a bridging carboxylate and a bridging water/hydroxide ion, thought to be the nucleophile that hydrolyzes the AHLs to ring-opened products, which can no longer act as quorum signals.

Bacillus thuringiensis↗