Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.184 (LasR)
 897 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In recent years it has become clear that the production of N-acyl homoserine lactones (N-AHLs) is widespread in Gram-negative bacteria. These molecules act as diffusible chemical communication signals (bacterial pheromones) which regulate diverse physiological processes including bioluminescence, antibiotic production, plasmid conjugal transfer and synthesis of exoenzyme virulence factors in plant and animal pathogens. The paradigm for N-AHL production is in the bioluminescence (lux) phenotype of Photobacterium fischeri (formerly classified as Vibrio fischeri) where the signalling molecule N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) is synthesized by the action of the LuxI protein. OHHL is thought to bind to the LuxR protein, allowing it to act as a positive transcriptional activator in an autoinduction process that physiologically couples cell density (and growth phase) to the expression of the bioluminescence genes. Based on the growing information on LuxI and LuxR homologues in other N-AHL-producing bacterial species such as Erwinia carotovora, Pseudomonas aeruginosa, Yersinia enterocolitica, Agrobacterium tumefaciens and Rhizobium leguminosarum, it seems that analogues of the P. fischeri lux autoinducer sensing system are widely distributed in bacteria. The general physiological function of these simple chemical signalling systems appears to be the modulation of discrete and diverse metabolic processes in concert with cell density. In an evolutionary sense, the elaboration and action of these bacterial pheromones can be viewed as an example of multicellularity in prokaryotic populations.
 ...
PMID:The bacterial 'enigma': cracking the code of cell-cell communication. 747 57

Serratia sp. ATCC 39006 produces two secondary metabolite antibiotics, 1-carbapen-2-em-3-carboxylic acid (Car) and the red pigment, prodigiosin (Pig). We have previously reported that production of Pig and Car is controlled by N-acyl homoserine lactone (N-AHL) quorum sensing, with synthesis of N-AHLs directed by the LuxI homologue SmaI, and is also regulated by Rap, a member of the SlyA family. We now describe further characterization of the SmaI quorum-sensing system and its connection with other regulatory mechanisms. We show that the genes responsible for biosynthesis of Pig, pigA-O, are transcribed as a single polycistronic message in an N-AHL-dependent manner. The smaR gene, transcribed convergently with smaI and predicted to encode the LuxR homologue partner of SmaI, was shown to possess a negative regulatory function, which is uncommon among the LuxR-type transcriptional regulators. SmaR represses transcription of both the pig and car gene clusters in the absence of N-AHLs. Specifically, we show that SmaIR exerts its effect on car gene expression via transcriptional control of carR, encoding a pheromone-independent LuxR homologue. Transcriptional activation of the pig and car gene clusters also requires a functional Rap protein, but Rap dependency can be bypassed by secondary mutations. Transduction of these suppressor mutations into wild-type backgrounds confers a hyper-Pig phenotype. Multiple mutations cluster in a region upstream of the pigA gene, suggesting this region may represent a repressor target site. Two mutations mapped to genes encoding pstS and pstA homologues, which are parts of a high-affinity phosphate transport system (Pst) in Escherichia coli. Disruption of pstS mimicked phosphate limitation and caused concomitant hyper-production of Pig and Car, which was mediated, in part, through increased transcription of the smaI gene. The Pst and SmaIR systems define distinct, yet overlapping, regulatory circuits which form part of a complex regulatory network controlling the production of secondary metabolites in Serratia ATCC 39006.
 ...
PMID:Phosphate availability regulates biosynthesis of two antibiotics, prodigiosin and carbapenem, in Serratia via both quorum-sensing-dependent and -independent pathways. 1251 8

Bacteria commonly use diffusible signal molecules to synchronise their behaviour by facilitating population dependent co-ordination. This cell-to-cell signalling mechanism is known as quorum sensing (QS) and provides a way of ensuring that certain genes are 'switched on' only when a certain signal concentration (typically corresponding to a large population density) has been reached. In this paper we focus on the QS system of the human pathogen Pseudomonas aeruginosa, which employs a complex hierarchy of QS signalling systems, which regulate the formation of multiple exoproducts, swarming and biofilm differentiation. In P. aeruginosa, the signal molecules are N-acylated homoserine lactones (AHLs; e.g., N-(3-oxododecanoyl)-homoserine lactone [3-oxo-C12-HSL]), which bind to transcriptional regulator proteins (LasR in the case of 3-oxo-C12-HSL) to activate the expression of target genes including lasI, which codes for the 3-oxo-C12-HSL synthase. Since the virulence of P. aeruginosa is controlled by QS, agents (QSBs) designed to block this cell-to-cell communication have potential as novel antibacterials. By drawing on existing models for the reaction kinetics of this system, we model a growing population subject to treatment with two kinds of QSB, together with a conventional antibiotic. The first kind of QSB is assumed to act by diffusing through the cell membrane and then destabilising/sequestering LasR, while the second kind remains outside the cell and degrades the AHL signal molecule itself. Numerical and mathematical analysis of the resulting systems of ordinary differential equations reveals in particular that, while a sufficiently high dose of QSB is, in all cases considered, able to reduce the AHL concentration (and hence virulence) to a negligible level, the qualitative response to treatment is sensitive to parameter values.
 ...
PMID:Mathematical modelling of therapies targeted at bacterial quorum sensing. 1549 75

Parallel solution-phase synthesis of sulfide AHL analogues (10a-s) by one-pot or a sequential approach is reported. The corresponding sulfoxides 13a-e and sulfones 14a-e were prepared to expand the diversity of the 19-member array of sulfides . Likewise, dithianes 12a-c were prepared with similarity both to sulfides 10a-s and to bioactive structures from garlic. Design and biological screening of all compounds presented in this work targeted inhibition of quorum-sensing comprising competitive inhibition of transcriptional regulators LuxR and LasR. The design was based on critical interactions within the binding-site and structural motifs in molecular components isolated from garlic, 7 and 8, shown to be quorum-sensing inhibitors but not antibiotics. A potent quorum-sensing inhibitor N-(heptylsulfanylacetyl)-l-homoserine lactone (10c) was identified. Together with data collected for the other analogues, the resulting structure-activity relationship led to a hypothesis in which competitive binding was assumed.
 ...
PMID:Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic. 1563 67

The biological control bacterium Pseudomonas chlororaphis (aureofaciens) strain 30-84 employs two quorum sensing (QS) systems: PhzR/PhzI regulates the production of the antibiotics phenazine-1-carboxylic acid, 2-hydroxy-phenazine-1-carboxylic acid, and 2-hydroxy-phenazine, whereas CsaR/CsaI regulates currently unknown aspects of the cell surface. Previously characterized derivatives of strain 30-84 with mutations in each QS system and in the phenazine biosynthetic genes were screened for their ability to form surface-attached biofilm populations in vitro, using microtiter plate and flow cell biofilm assays, and on seeds and roots. Results from in vitro, seed, and root studies demonstrated that the PhzR/PhzI and the CsaR/CsaI QS regulatory systems contribute to the establishment of biofilms, with mutations in PhzR/PhzI having a significantly greater effect than mutations in CsaR/CsaI. Interestingly, phenazine antibiotic production was necessary for biofilm formation to the same extent as the PhzR/PhzI QS system, suggesting the loss of phenazines was responsible for the majority of the biofilm defect in these mutants. In vitro analysis indicated that genetic complementation or AHL addition to the growth medium restored the ability of the AHL synthase phzI mutant to form biofilms. However, only phenazine addition or genetic complementation of the phenazine biosynthetic mutation in trans restored biofilm formation by mutants defective in the transcriptional activator phzR or the phzB structural mutant. QS and phenazine production were also involved in the establishment of surface-attached populations on wheat seeds and plant roots, and, as observed in vitro, the addition of AHL extracts restored the ability of phzI mutants, but not phzR mutants, to form surface attached populations on seeds. Similarly, the presence of the wild type in mixtures with the mutants restored the ability of the mutants to colonize wheat roots, demonstrating that AHL and/or phenazine production by the wild-type population could complement the AHL- and phenazine-deficient mutants in situ. Together, these data demonstrate that both QS systems are involved in the formation of surface-attached populations required for biofilm formation by P. chlororaphis strain 30-84, and indicate a new role for phenazine antibiotics in rhizosphere community development beyond inhibition of other plant-associated microorganisms.
 ...
PMID:Quorum sensing and phenazines are involved in biofilm formation by Pseudomonas chlororaphis (aureofaciens) strain 30-84. 1689 5

Gram-negative bacteria predominantly use two types of quorum sensing (QS) systems--LuxI-LuxR, responsible for synthesis of N-acylhomoserine lactones (AHL or AI-1 signal molecule), and LuxS, which makes furanones (AI-2 signal molecule). We showed that LuxS and two LuxI-LuxR (YtbIR and YpsIR) systems are functional in Y. pestis. Four different AHL molecules were detected in Y. pestis extracts using TLC bioassays. Our data suggest that YtbIR is responsible for the production of long chain AHLs. Confocal laser scanning microscopy showed that biofilm formation is decreased in an ytbIR ypsIR luxS mutant. Two-dimensional gel electrophoresis revealed altered levels of protein expression in a Y. pestis triple QS mutant at 26 degrees C and 37 degrees C.
 ...
PMID:Functional quorum sensing systems affect biofilm formation and protein expression in Yersinia pestis. 1796 14

By secretion and detection of a series of signaling molecules, bacteria are able to coordinate gene expression as a community, to regulate a variety of important phenotypes, from virulence factor production to biofilm formation to symbiosis related behaviours such as bioluminescence. This widespread signaling mechanism is called quorum sensing. There are several quorum sensing systems described in Serratia. Serratia marcescens AS-1, isolated from soil, had the LuxI/LuxR homologues called SpnI/SpnR. S. marcescens AS-1 produced two kinds of N-acyl-L-homoserine lactones, N-hexanoyl-L-homoserine lactone and N-(3-oxohexanoyl)-L-homoserine lactone as signal molecules, which involved in quorum sensing to control the gene expression in response to increased cell density. By gene replacement method, the spnR mutant was constructed, named S. marcescens AS-1R. SpnR acted as a negative regulator for the production of prodigiosin, swarming motility and biofilm formation, which were regulated by quorum sensing. Halogenated furanone, known as a natural inhibitor of quorum sensing, could effectively inhibit the quorum sensing of S. marcescens AS-1 but without interrupting AHL-SpnR interaction. All results will be helpful to understand the mechanisms of halogenated furanone inhibition on quorum sensing and the potential application of halogenated furanone in effectively preventing infection disease caused by Serratia strains.
 ...
PMID:The function of SpnR and the inhibitory effects by halogenated furanone on quorum sensing in Serratia marcescens AS-1. 1847 69

A virtual screening, involving flexible docking sequences within the LuxR, TraR and LasR binding sites, was used as a structural binding sites similarity filter to specifically target conserved residues in the proteins of the LuxR family (namely Tyr62, Trp66, Tyr70, Asp79, Trp94 for LuxR). This docking-based screening, employing a genetic algorithm, was performed on a 2344 chemical compounds library, together with empirical binding free energy (DeltaG(bind)) calculations. Docking results were analysed, and the compounds detected with reproducible low DeltaG(bind) values or identified as being in the top 120 for most of the docking sequences, were selected as hits candidates which interact with conserved residues. Biological evaluation with LuxR-dependent quorum sensing led to the discovery of some new inhibitors, namely tamoxifen, sertraline, pimethixene, terfenadine, fendiline and calmidazolium. Notably, calmidazolium was identified as one of the most potent AHL-structurally unrelated inhibitors of LuxR-dependent quorum sensing, with an IC(50) value of 7.0+/-0.2 microM.
 ...
PMID:LuxR-dependent quorum sensing: computer aided discovery of new inhibitors structurally unrelated to N-acylhomoserine lactones. 2061 99

Surface adhered bacterial colonies or biofilms are an important problem in medical and food industries. Bacteria use a chemical language to monitor their quorum and to express virulence factors, which eventually help them in colonization and manifestation of an infection. The LasR-LasI and RhlR-RhlI quorum-sensing (QS) systems of Pseudomonas aeruginosa control expression of virulence factors in a population density-dependent fashion. In this study we investigated the role of synthetic analogs to RhlR-RhlI system of P. aeruginosa strains (PAO-1; wild-type and mutants JP-1, PDO-100, and JP-2) responsible for production of acyl-homoserine lactones-2; butanol homoserine lactone (AHL-2; C(4)-HSL). We synthesized double (QS1207) and single (QS0108) sulfur analogs against (C(4)-HSL; AHL-2), an autoinducer of Pseudomonas QS system. Extensive biological investigation of these analogs suggested a growth promoting activity for these analogs in Pseudomonas controlling biofilm production and exo-protease secretion. We hypothesized that these thiolactone analogs could be potentially utilized as potent drug-delivery vehicles against biofilm-producing pathogens. As a proof of principle we conjugated the single sulfur analog QS0108 with the broad-spectrum antibiotic, ciprofloxacin (QS0108-Cip). The QS analog-antibiotic conjugate was significantly more effective at disrupting both the nascent and mature biofilms of P. aeruginosa than the free antibiotic.
 ...
PMID:Design, synthesis, and a novel application of quorum-sensing agonists as potential drug-delivery vehicles. 2088 84

Quorum sensing (QS) in a bacterial population is activated when extracellular concentration of QS signal reaches a threshold, but how this threshold is determined remains largely unknown. In this study, we report the identification and characterization of a novel anti-activator encoded by qslA in Pseudomonas aeruginosa. The null mutation of qslA elevated AHL-dependent QS and PQS signalling, increased the expression of QS-dependent genes, and enhanced the virulence factor production and pathogenicity. We further present evidence that modulation of QS by QslA is due to protein-protein interaction with LasR, which prevents LasR from binding to its target promoter. QslA also influences the threshold concentration of QS signal needed for QS activation; in the absence of qslA, QS is activated by nine times less N-3-oxo-dodecanoyl-homoserine lactone (3-oxo-C12-HSL) than that in wild type. The findings from this study depict a new mechanism that governs the QS threshold in P. aeruginosa.
 ...
PMID:Anti-activator QslA defines the quorum sensing threshold and response in Pseudomonas aeruginosa. 2139 32


1 2 3 Next >>