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Results for “Quorum Sensing”

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PubMed2005

Biologically active fluorescent farnesol analogs.

We describe ten polyene analogs of farnesol, typified by 3,7,11-trimethyl-2,4,6,8,10-dodecapentenaldehyde oxime, which preserve the length, cross-section, and approximate hydrophobicity of farnesol. Four of the ten display strong quorum-sensing activity in the human pathogen Candida albicans, with IC(50) values for inhibition of germ-tube formation as low as 10 microM. The polyenes display absorption maxima between 320 and 380 nm, with the extinction coefficients for the oximes approaching 100,000. All but two of the analogs are fluorescent, with excitation maxima varying over the range of 320-370 nm. Oxime anti-4, which can undergo fluorescence excitation at wavelengths beyond 400 nm, is demonstrated to be useful for confocal fluorescence microscopic imaging of fungal cells. The farnesol analogs are also expected to be useful for detection of farnesol binding proteins and in determination of farnesol pharmacokinetics.

Candida albicans↗

PubMed2006

Stereoisomers of P. aeruginosa autoinducer analog to probe the regulator binding site.

Quorum sensing (QS) regulates the production of virulence factors and the maturation of biofilms in many bacteria, including Pseudomonas aeruginosa. The QS cascade is activated by the interaction of bacterial signaling molecules, called autoinducers (AIs), with their corresponding regulatory proteins. Here, we report a series of studies to define the stereochemical preferences of synthetic agonists and perform docking studies to understand the microenvironment of the binding site in P. aeruginosa QS regulators. One of the key findings of this work is that the ring structure and the absolute and relative stereochemistries of the amide and hydroxyl groups dictate the agonist activity. This study aids in determining important structural and stereochemical characteristics necessary for interaction with the QS regulatory proteins, thus expanding our understanding of their inducer binding sites.

Amino Alcohols↗

PubMed2004

Approaches for trigger-inducible viral transgene regulation in gene-based tissue engineering.

Recent advances in mammalian transgene expression dosing have resulted in a portfolio of mutually compatible systems that can adjust therapeutic transgene levels in response to antibiotics, hormone analogues, quorum-sensing messengers and secondary metabolites. The molecular merger of trigger-inducible expression technology with the latest generation of virus-derived transduction systems has enabled unmatched clinical interventions to shape desired therapeutic cell and tissue phenotypes for the treatment of complex human diseases.

Animals↗

PubMed2005

Control of the Ralstonia solanacearum Type III secretion system (Hrp) genes by the global virulence regulator PhcA.

Expression of several virulence factors in the plant pathogen bacterium Ralstonia solanacearum is controlled by a complex regulatory network, at the center of which is PhcA. We provide genetic evidence that PhcA also represses the expression of hrp genes that code for the Type III protein secretion system, a major pathogenicity determinant in this bacterium. The repression of hrp genes in complete medium is relieved in a phcA mutant and two distinct signals, a quorum-sensing signal and complex nitrogen sources, appear to trigger this PhcA-dependent repression. This control of hrp gene expression by PhcA is realized at the level of the HrpG regulatory protein.

Bacterial Proteins↗

PubMed2005

Quorum quenching enzyme activity is widely conserved in the sera of mammalian species.

Acyl-homoserine lactone (AHL) quorum sensing signals play a key role in synchronizing virulence gene expression in Pseudomonas aeruginosa, which could cause fatal bloodstream infections. We showed that AHL inactivation activity, albeit with variable efficiency, was conserved in the serum samples of all the 6 tested mammalian animals. High-performance liquid chromatography and mass spectrometry analyses revealed that mammalian sera had a lactonase-like enzyme(s), which hydrolyzed the lactone ring of AHL to produce acyl homoserine, with enzyme properties reminiscent of paraoxonases (PONs). We further showed that the animal cell lines expressing three mouse PON genes, respectively, displayed strong AHL degradation activities.

4-Butyrolactone↗

PubMed2005

Identification of N-acylhomoserine lactones in mucopurulent respiratory secretions from cystic fibrosis patients.

Pseudomonas aeruginosa and species of the Burkholderia cepacia complex are the primary bacterial pathogens contributing to lung disease in patients with cystic fibrosis. Quorum sensing systems using N-acyl homoserine lactone (AHL) signal molecules are involved in the regulation of a number of virulence factors in these species. Extracts of mucopurulent respiratory secretions from 13 cystic fibrosis patients infected with P. aeruginosa and/or strains of the B. cepacia complex were fractionated using reverse-phase fast pressure liquid chromatography and analyzed for the presence of AHLs using a traI-luxCDABE-based reporter that responds to AHLs with acyl chains ranging between 4 and 12 carbons. Using this assay system, a broad range of AHLs were detected and identified despite being present at low concentrations in limited sample volumes. N-(3-oxo-dodecanoyl)-l-homoserine lactone, N-(3-oxo-decanoyl)-l-homoserine lactone and N-octanoyl-l-homoserine lactone (OHL) were the AHLs most frequently identified. OHL and N-decanoyl-l-homoserine lactone were detected in nanomolar concentrations compared to picomolar amounts of the 3-oxo-derivatives of the AHLs identified.

Burkholderia cepacia↗

PubMed2005

Sensor domain of histidine kinase ComD confers competence pherotype specificity in Streptoccoccus pneumoniae.

Competence for genetic transformation in Streptococcus pneumoniae is regulated by a quorum-sensing mechanism involving the pheromone competence stimulating peptide (CSP) encoded by comC and a two-component signal transduction system, ComD-ComE (TCS12). In the presence of CSP, the transmembrane histidine kinase ComD receptor activates the response regulator ComE. The comC, comD and comE genes are part of an operon denoted as comCDE. In this work, the comCDE locus of 17 S. pneumoniae strains was characterized by DNA sequencing. Two major allelic combinations, comC1-comD1 and comC2-comD2 were present. Two further allelic combinations, comC1-comD3 and comC1-comD4, were also present. Comparison of the deduced amino acid sequences of the four ComD allelic variants showed that all variations are localized in the N-terminal sensor domain. In order to have the four comD alleles in the same genetic background, we constructed four different isogenic strains in which comC was deleted and the DNA encoding the sensor domain of ComD was exchanged. To formally demonstrate that the sensor domain of ComD is responsible for competence pherotype specificity, CSP-1 and CSP-2 peptides were used to induce competence in the isogenic strains: (i) strains expressing the ComD1, ComD3 and ComD4 variants were induced to competence by CSP1; (ii) the strain expressing ComD2 was induced by CSP2. Moreover, cross-induction of competence by both CSPs was observed in the ComD2 and ComD3-carrying strains in the presence of high CSP doses. This is the first formal confirmation that the ComD sensor domain is responsible for competence pherotype specificity in S. pneumoniae.

Alleles↗

PubMed2005

Osmotic stress and phosphate limitation alter production of cell-to-cell signal molecules and rhamnolipid biosurfactant by Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, rhamnolipid production is controlled by the quorum-sensing system RhlRI, which itself depends on LasRI. These systems use cell-to-cell signal molecules: N-butyryl-l-homoserine lactone (C4-HSL) and N-(3-oxododecanoyl)-l-homoserine lactone (3OC(12)-HSL), respectively. Whereas both HSLs were produced in M63 medium, rhamnolipid synthesis was not achieved. Phosphate limitation reduced the HSL concentrations, while allowing rhamnolipid production. Hyperosmotic shock applied during the exponential growth phase stopped the accumulation of 3OC(12)-HSL, and prevented C4-HSL and rhamnolipid production. These defects result from lower expression of genes involved in C4-HSL and rhamnolipid syntheses. The osmoprotectant glycine betaine partially restored C4-HSL and rhamnolipid production.

4-Butyrolactone↗

PubMed2005

Salmonella stress management and its relevance to behaviour during intestinal colonisation and infection.

The enteric pathogen Salmonella enterica is exposed to a number of stressful environments during its life cycle within and outside its various hosts. During intestinal colonisation Salmonella is successively exposed to acid pH in the stomach, to the detergent-like activity of bile, to decreasing oxygen supply, to the presence of multiple metabolites produced by the normal gut microflora and finally it is exposed to cationic antimicrobial peptides present on the surface of epithelial cells. There are four major regulators controlling relevant stress responses in Salmonella, namely RpoS, PhoPQ, Fur and OmpR/EnvZ. Except for Fur, inactivation of genes encoding the other stress regulators results in attenuated virulence and such mutants can therefore be considered as vaccine candidates. In contrast, a decrease in oxygen supply monitored by Fnr and ArcAB, or oxidative stress controlled by OxyR and SoxRS is not regarded as a stress associated with host colonisation since inactivation of either of these systems does not result in reductions in colonisation. The role of quorum-sensing through luxS and sdiA is also considered as a regulator of virulence and colonisation.

Animals↗

PubMed2005

Effect of temperature and glucose concentration on the N-butanoyl-L-homoserine lactone production by Aeromonas hydrophila.

N-butanoyl-L-homoserine lactone (C4-HSL) production by Aeromonas hydrophila 519 has been established. C4-HSL production at 22 and 30 degrees C was found after 20-24 h of incubation corresponding to a population density of ca. 10(8)-10(9) cfu/ml, respectively. Reduced C4-HSL production was noted after 72 h of incubation at 12 degrees C when the culture reached ca. 10(9) cfu/ml. No C4-HSL production was detected at 37 degrees C, although a dense population was obtained. In LB broth supplemented with 0.1% and 0.5% glucose, C4-HSL production was noted whereas with 1% glucose no C4-HSL was detected although a high colony count was obtained. In the latter culture residual levels of glucose (0.65%) were found after 43 h whereas in the 0.1% and 0.5% supplemented LB, glucose was quickly consumed which may have stimulated C4-HSL production. In conclusion, the present study shows an effect of environmental conditions (temperature, glucose concentration) on the C4-HSL production and warrants further investigation to elucidate the effect of external conditions on production of AHL signal molecules to reveal the relevance of quorum sensing in, e.g. foods.

4-Butyrolactone↗

PubMed2005

The mathematical properties of the quasi-chemical model for microorganism growth-death kinetics in foods.

Knowledge of the mathematical properties of the quasi-chemical model [Taub, Feeherry, Ross, Kustin, Doona, 2003. A quasi-chemical kinetics model for the growth and death of Staphylococcus aureus in intermediate moisture bread. J. Food Sci. 68 (8), 2530-2537], which is used to characterize and predict microbial growth-death kinetics in foods, is important for its applications in predictive microbiology. The model consists of a system of four ordinary differential equations (ODEs), which govern the temporal dependence of the bacterial life cycle (the lag, exponential growth, stationary, and death phases, respectively). The ODE system derives from a hypothetical four-step reaction scheme that postulates the activity of a critical intermediate as an antagonist to growth (perhaps through a quorum sensing biomechanism). The general behavior of the solutions to the ODEs is illustrated by several examples. In instances when explicit mathematical solutions to these ODEs are not obtainable, mathematical approximations are used to find solutions that are helpful in evaluating growth in the early stages and again near the end of the process. Useful solutions for the ODE system are also obtained in the case where the rate of antagonist formation is small. The examples and the approximate solutions provide guidance in the parameter estimation that must be done when fitting the model to data. The general behavior of the solutions is illustrated by examples, and the MATLAB programs with worked examples are included in the appendices for use by predictive microbiologists for data collected independently.

Food Microbiology↗

PubMed2004

A quasi-chemical model for the growth and death of microorganisms in foods by non-thermal and high-pressure processing.

Predictive microbial models generally rely on the growth of bacteria in laboratory broth to approximate the microbial growth kinetics expected to take place in actual foods under identical environmental conditions. Sigmoidal functions such as the Gompertz or logistics equation accurately model the typical microbial growth curve from the lag to the stationary phase and provide the mathematical basis for estimating parameters such as the maximum growth rate (MGR). Stationary phase data can begin to show a decline and make it difficult to discern which data to include in the analysis of the growth curve, a factor that influences the calculated values of the growth parameters. In contradistinction, the quasi-chemical kinetics model provides additional capabilities in microbial modelling and fits growth-death kinetics (all four phases of the microbial lifecycle continuously) for a general set of microorganisms in a variety of actual food substrates. The quasi-chemical model is differential equations (ODEs) that derives from a hypothetical four-step chemical mechanism involving an antagonistic metabolite (quorum sensing) and successfully fits the kinetics of pathogens (Staphylococcus aureus, Escherichia coli and Listeria monocytogenes) in various foods (bread, turkey meat, ham and cheese) as functions of different hurdles (a(w), pH, temperature and anti-microbial lactate). The calculated value of the MGR depends on whether growth-death data or only growth data are used in the fitting procedure. The quasi-chemical kinetics model is also exploited for use with the novel food processing technology of high-pressure processing. The high-pressure inactivation kinetics of E. coli are explored in a model food system over the pressure (P) range of 207-345 MPa (30,000-50,000 psi) and the temperature (T) range of 30-50 degrees C. In relatively low combinations of P and T, the inactivation curves are non-linear and exhibit a shoulder prior to a more rapid rate of microbial destruction. In the higher P, T regime, the inactivation plots tend to be linear. In all cases, the quasi-chemical model successfully fit the linear and curvi-linear inactivation plots for E. coli in model food systems. The experimental data and the quasi-chemical mathematical model described herein are candidates for inclusion in ComBase, the developing database that combines data and models from the USDA Pathogen Modeling Program and the UK Food MicroModel.

Bacteria↗

PubMed2004

Cell density--dependent regulation: basic principles and effects on the virulence of Gram-positive cocci.

PRINCIPLES: Quorum sensing (QS) regulation appears to be a consequence of interbacterial communication by which bacteria of one or even different species learn about their current population density and react in a defined way to that information. QS-regulation is a three step process: in the first step specific signaling molecules are produced and secreted to the exterior space. In the second step, the molecules accumulate e.g. with growing population density. In the last step, a supra-threshold concentration of the molecules is extra- or intra-cellularly sensed by the bacteria and leads to a cascade of regulatory activities. While Gram-negative bacteria can employ five or more different chemical classes of signaling molecules, Gram-positive cocci predominantly use special oligopeptides for specific signaling. DESCRIPTIONS: Examples of QS-regulatory effects on virulence factor expression in Staphylococcus aureus, Streptococcus mutans, and Enterococcus faecalis are given. In these bacteria, QS-regulation appears to be crucial for displaying tissue invasiveness and/or biofilm formation. APPLICATIONS: The high specificity of the initial signal sensing and the importance for expressing special virulence traits make this type of gene expression control a promising target for the development of novel therapeutics. The options for such therapies are critically discussed based on practical experiences with interference in S. aureus QS-regulation.

Animals↗

PubMed2004

Pseudomonas aeruginosa and Burkholderia cepacia in cystic fibrosis: genome evolution, interactions and adaptation.

The Gram-negative bacteria Pseudomonas aeruginosa and Burkholderia cepacia are opportunistic human pathogens that are responsible for severe nosocomial infections in immunocompromised patients and are the major pathogens in cystic fibrosis (CF). The two bacteria not only inhabit the same environmental niches but can also form mixed biofilms in the lungs of CF patients. Hence, it appears very likely that the two organisms are capable of interacting with each other. Work of the past few years has shown that both bacteria utilize quorum-sensing systems, which rely on N-acyl-homoserine lactone signal molecules, to control the expression of virulence factors and biofilm development. Most importantly, evidence has been presented that these signal molecules also serve as a universal language for communication between the two organisms. Moreover, analyses of the diversity in P. aeruginosa revealed the presence of genome islands that contain genes that are highly homologous to genes identified in strains of Burkholderia sp. This finding suggests that there is a frequent exchange of genetic material between the two organisms.

4-Butyrolactone↗

PubMed2006

4-quinolone signalling in Pseudomonas aeruginosa: old molecules, new perspectives.

In Pseudomonas aeruginosa, diverse virulence determinants and secondary metabolites are regulated via the action of a hierarchical quorum-sensing system which integrates two chemically distinct classes of signal molecules, the N-acylhomoserine lactones (AHLs) and the 4-quinolones (4Qs). Synthesis of the pseudomonas quinolone signal, 2-heptyl-3-hydroxy-4-quinolone (PQS) depends on the pqsABCDE locus which is responsible for generating multiple 4Qs including 2-heptyl-4-quinolone (HHQ), the immediate PQS precursor. Exported HHQ is taken up by adjacent bacterial cells and converted into PQS by PqsH, a putative mono-oxygenase. In addition, PQS regulates its own production by driving the expression of pqsABCDE through a direct interaction with PqsR (MvfR). PQS regulates diverse target genes including those coding for elastase, rhamnolipid, the PA-IL lectin and pyocyanin via the action of PqsE as well as influencing biofilm development and impacting on cellular fitness. Furthermore, 4Q signalling is not restricted to P. aeruginosa raising the possibility of cross-talk with other related bacterial species which occupy similar ecological niches.

4-Quinolones↗

PubMed2004

Stress in recombinant protein producing yeasts.

It is well established today that heterologous overexpression of proteins is connected with different stress reactions. The expression of a foreign protein at a high level may either directly limit other cellular processes by competing for their substrates, or indirectly interfere with metabolism, if their manufacture is blocked, thus inducing a stress reaction of the cell. Especially the unfolded protein response (UPR) in Saccharomyces cerevisiae (as well as some other yeasts) is well documented, and its role for the limitation of expression levels is discussed. One potential consequence of endoplasmatic reticulum folding limitations is the ER associated protein degradation (ERAD) involving retrotranslocation and decay in the cytosol. High cell density fermentation, the typical process design for recombinant yeasts, exerts growth conditions that deviate far from the natural environment of the cells. Thus, different environmental stresses may be exerted on the host. High osmolarity, low pH and low temperature are typical stress factors. Whereas the molecular pathways of stress responses are well characterized, there is a lack of knowledge concerning the impact of stress responses on industrial production processes. Accordingly, most metabolic engineering approaches conducted so far target at the improvement of protein folding and secretion, whereas only few examples of cell engineering against general stress sensitivity were published. Apart from discussing well-documented stress reactions of yeasts in the context of heterologous protein production, some more speculative topics like quorum sensing and apoptosis are addressed.

Biotechnology↗

PubMed2006

The cytostat: A new way to study cell physiology in a precisely defined environment.

In a cytostat, a continuous culture is monitored and controlled by an automated flow cytometer system, based on the determination of the cell concentration and the single cell property distribution of the growing cell population. The growing culture can be maintained at steady state even at such low cell concentrations that the bioreactor medium composition is negligibly changed by the few cells. Therefore, the cell environment is precisely defined by the feed composition since products of cell growth are not present in significant amounts. Effects on cell growth of nutrients, of toxic compounds such as drugs, or of products made by the cells, if added to the feed medium, can be readily isolated. Using the cytostat, it is shown here that ethanol assumes the triggering function for the increase in cell size in Saccharomyces cerevisiae normally only seen at critical growth rates above critical cell densities. This suggests that ethanol assumes a quorum sensing function on cell growth when a critical cell density is reached.

Bioreactors↗

PubMed2005

Attaching-effacing bacteria in animals.

Enteric bacteria with a demonstrable or potential ability to form attaching-effacing lesions, so-called attaching-effacing (AE) bacteria, have been found in the intestinal tracts of a wide variety of warm-blooded animal species, including man. In some host species, for example cattle, pigs, rabbits and human beings, attaching-effacing Escherichia coli (AEEC) have an established role as enteropathogens. In other host species, AE bacteria are of less certain significance. With continuing advances in the detection and typing of AE strains, the importance of these bacteria for many hosts is likely to become clearer. The pathogenic effects of AE bacteria result from adhesion to the intestinal mucosa by a variety of mechanisms, culminating in the formation of the characteristic intimate adhesion of the AE lesion. The ability to induce AE lesions is mediated by the co-ordinated expression of some 40 bacterial genes organized within a so-called pathogenicity island, known as the "Locus for Enterocyte Effacement". It is also believed that the production of bacterial toxins, principally Vero toxins, is a significant virulence factor for some AEEC strains. Recent areas of research into AE bacteria include: the use of Citrobacter rodentium to model human AEEC disease; quorum-sensing mechanisms used by AEEC to modulate virulence gene expression; and the potential role of adhesion in the persistent colonization of the intestine by AE bacteria. This review of AE bacteria covers their molecular biology, their occurrence in various animal species, and the diagnosis, pathology and clinical aspects of animal diseases with which they are associated. Reference is made to human pathogens where appropriate. The focus is mainly on natural colonization and disease, but complementary experimental data are also included.

Animals↗