Structure of a bacterial quorum-sensing transcription factor complexed with pheromone and DNA

Zhang, Rongguang; Pappas, Terina; Brace, Jennifer L.; Miller, Philip W.; Oulmassov, Tim; Molyneaux, John M.; Anderson, John C.; Bashkin, James K.; Winans, Stephen C.; Joachimiak, Andrzej

doi:10.1038/nature00833

Cited by 409 publications

(556 citation statements)

References 26 publications

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“…Importantly, the relative inhibition potencies of the various antagonists were found to directly correlate with the progressive repositioning of the Met89 side chain, a result that helps to explain how small changes in ligand structure can induce large changes in receptor activity (202). For other AHL receptors, including TraR and LasR, the native ligands are postulated to trigger a protein folding switch that is required for proper folding of the receptor, which enhances protein stability (175)(176)(177)(178)(179). In these cases, antagonists may function by promoting the adoption of nonnative conformations which could both prevent productive DNA-protein interactions and promote receptor degradation.…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

“…This is in agreement with studies demonstrating that even minor changes in the length or substituents of the acyl tail, which contributes to the binding affinity between the receptor and the ligand (11,166,(194)(195)(196), can have large effects on its activity (11,170,197). Alteration of the chirality of the lactone ring or substitutions of part or all of the lactone head group can also alter the activity of a given molecule for a given AHL receptor (11, 118, 165-167, 196, 197), likely because of important conserved intermolecular hydrogen bonds between the AHL lactone head group and the ligand-binding pockets of AHL receptors (175)(176)(177)(178)(179)(180). In addition to promoting ligand-receptor interaction, hydrogen bonding may also help to determine the type of activity exhibited by a given compound.…”

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

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Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

689

556

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SUMMARY Cell-cell communication, or quorum sensing, is a widespread phenomenon in bacteria that is used to coordinate gene expression among local populations. Its use by bacterial pathogens to regulate genes that promote invasion, defense, and spread has been particularly well documented. With the ongoing emergence of antibiotic-resistant pathogens, there is a current need for development of alternative therapeutic strategies. An antivirulence approach by which quorum sensing is impeded has caught on as a viable means to manipulate bacterial processes, especially pathogenic traits that are harmful to human and animal health and agricultural productivity. The identification and development of chemical compounds and enzymes that facilitate quorum-sensing inhibition (QSI) by targeting signaling molecules, signal biogenesis, or signal detection are reviewed here. Overall, the evidence suggests that QSI therapy may be efficacious against some, but not necessarily all, bacterial pathogens, and several failures and ongoing concerns that may steer future studies in productive directions are discussed. Nevertheless, various QSI successes have rightfully perpetuated excitement surrounding new potential therapies, and this review highlights promising QSI leads in disrupting pathogenesis in both plants and animals.

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Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

Section: Inhibition Of Signal Detection Synthetic Signal Analogues Anmentioning

confidence: 99%

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

LaSarre

Federle

2013

Microbiol Mol Biol Rev

689

556

View full text Add to dashboard Cite

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“…The last open reading frame of this operon codes for the QS transcription activator TraR. Binding of TraR to its cognate autoinducer is thought to occur only within a narrow window of time during traR mRNA translation when the newly formed protein chain tightly winds around a single molecule of Agrobacterium autoinducer (AAI) [18][19][20]. This total engulfment of AAI molecule makes formation of the TraR-AAI complex (TraR*) practically irreversible.…”

Section: Synopsismentioning

confidence: 99%

Transition to Quorum Sensing in an Agrobacterium Population: A Stochastic Model

Goryachev¹,

Toh²,

Wee³

et al. 2005

PLoS Comp Biol

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Understanding of the intracellular molecular machinery that is responsible for the complex collective behavior of multicellular populations is an exigent problem of modern biology. Quorum sensing, which allows bacteria to activate genetic programs cooperatively, provides an instructive and tractable example illuminating the causal relationships between the molecular organization of gene networks and the complex phenotypes they control. In this work we-to our knowledge for the first time-present a detailed model of the population-wide transition to quorum sensing using the example of Agrobacterium tumefaciens. We construct a model describing the Ti plasmid quorum-sensing gene network and demonstrate that it behaves as an ''on-off'' gene expression switch that is robust to molecular noise and that activates the plasmid conjugation program in response to the increase in autoinducer concentration. This intracellular model is then incorporated into an agent-based stochastic population model that also describes bacterial motion, cell division, and chemical communication. Simulating the transition to quorum sensing in a liquid medium and biofilm, we explain the experimentally observed gradual manifestation of the quorum-sensing phenotype by showing that the transition of individual model cells into the ''on'' state is spread stochastically over a broad range of autoinducer concentrations. At the same time, the population-averaged values of critical autoinducer concentration and the threshold population density are shown to be robust to variability between individual cells, predictable and specific to particular growth conditions. Our modeling approach connects intracellular and population scales of the quorum-sensing phenomenon and provides plausible answers to the long-standing questions regarding the ecological and evolutionary significance of the phenomenon. Thus, we demonstrate that the transition to quorum sensing requires a much higher threshold cell density in liquid medium than in biofilm, and on this basis we hypothesize that in Agrobacterium quorum sensing serves as the detector of biofilm formation.

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“…The study revealed the main anchoring sites of 1 with different aminoacid residues and the protein structural changes induced by complexation that increases the complex affinity to specific DNA-binding sites. 7 However, little is known about the first interactions of the signaling substance with the cells, especially at the membrane level. Radioisotope-labeled acyl-HSLs studies provided evidence that short chain acyl-HSLs (4 carbon acyl side chain) cross the cell membrane through diffusion, while longer ones are captured through active pumping, probably mediated by permeases or carrying proteins.…”

Section: Introductionmentioning

confidence: 99%

Binding Events of (S)-N-(3-Oxo-octanoyl)-homoserine Lactone with Agrobacterium tumefaciens Mutant Cells Studied by Saturation Transfer Difference NMR

Cabeça¹,

Pomini²,

Cruz³

et al. 2011

J. Braz. Chem. Soc.

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Quorum-sensing é um fenômeno de comunicação amplamente estudado em bactérias, o qual envolve a produção e detecção de substâncias sinalizadoras que dependem do comportamento da colônia e da densidade celular. No presente trabalho, a interação entre a substância sinalizadora (S)-N-(3-oxo-octanoil)-HSL e a membrana celular da A. tumefaciens NTL4(pZLR4) foi estudada utilizando a espectroscopia de RMN da diferença de transferência de saturação (STD-NMR). O mapa do epitopo da substância foi obtido, mostrando que a cadeia hidrofóbica acila apresentou o mais importante ponto de interação. Os resultados foram interpretados em comparação a um sistema modelo de membrana, os lipossomas. Também foi analisado o uso da b-ciclodextrina como carreador da acil-HSL.Quorum-sensing is a widely studied communication phenomenon in bacteria, which involves the production and detection of signaling substances in relation with cell density and colony behavior. Herein, the membrane binding interactions of the signal (S)-N-(3-oxo-octanoyl)-HSL with A. tumefaciens NTL4(pZLR4) cells were studied using saturation transfer difference NMR spectroscopy (STD-NMR). The substance epitope map was obtained showing that the hydrophobic acyl chain is the most important interacting site for the signal and the cell membrane. Results were interpreted upon comparisons with a simpler system, using liposomes as membrane models. Some insights on the use of b-cyclodextrin as acyl-HSL carrier were also provided. Keywords: STD-NMR, acyl-homoserine lactone, membrane interactions IntroductionIt is well recognized nowadays that bacteria use quorum-sensing communication circuits to regulate a wide array of physiological activities. These processes include symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation and biofilm formation, among several other phenotypes crucial for bacterial survival and host infection. This phenomenon relies on the production of low molar mass signaling molecules usually related to cell density. In many Gram-negative bacteria the acyl-homoserine lactones (acyl-HSLs) are the most studied chemical signals. 1 In the quorum-sensing process, synthases (LuxI homologs) produce the signaling molecules, which diffuse from the cytoplasm to the near environment through the cellular membrane in the case of short chain acyl-HSLs or through active efflux pumping in long chain ones. 2 The acyl-HSL concentration is related to cell density, i.e., as the colony grows the metabolite concentration also increases due to the presence of new producing individuals. The process continues until a threshold concentration is reached, when the metabolites bind to transcriptional proteins (LuxR homologs) and the complex regulates gene expression. 3 Therefore, quorum-sensing allows whole bacterial populations to act coordinately, improving their chances of successful environment colonization.One of the most interesting quorum-sensing mechanisms was reported for Agrobacterium tumefaciens, a phytopathogen that induces crown gall tu...

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Structure of a bacterial quorum-sensing transcription factor complexed with pheromone and DNA

Cited by 409 publications

References 26 publications

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

Transition to Quorum Sensing in an Agrobacterium Population: A Stochastic Model

Binding Events of (S)-N-(3-Oxo-octanoyl)-homoserine Lactone with Agrobacterium tumefaciens Mutant Cells Studied by Saturation Transfer Difference NMR

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