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BioAssay: AID 686945

Broad Institute Quorum Sensing in Vibrio cholera: LuxO Inhibitor Probe Project

the production, release, detection, and response to extracellular signaling molecules called autoinducers. Quorum sensing allows bacteria to synchronously alter behavior in response to changes in the population density and species composition of the vicinal bacterial community. Quorum sensing controls collective behaviors including bioluminescence, sporulation, virulence factor production, and more ..
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AID: 686945
Data Source: Broad Institute (2132_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Screening Center Network, Assay Provider
BioAssay Version:
Deposit Date: 2013-04-18
Modify Date: 2013-09-19
Target
Depositor Specified Assays
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AIDNameTypeProbeComment
686936In vitro LuxO ATPase Assay Measured in Biochemical System Using Plate Reader - 2132-11_Inhibitor_Dose_DryPowder_Activityother 2 drypowder compounds at dose in 11 In vitro LuxO ATPase Assay measuring activity
686929Cholera Quorum: HTS for inducers of light production in the absence of autoinducers using BH1578 (luxS deficient, cqsA deficient) Measured in Microorganism System Using Plate Reader - 2132-01_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory 97 drypowder compounds at dose in Cholera Quorum HTS measuring activity set 2
686928Cytotoxicity at 24 hours in dose with HeLa cells Measured in Cell-Based System Using Plate Reader - 2132-02_Inhibitor_Dose_DryPowder_Activityconfirmatory 97 drypowder compounds at dose in 02 HeLa 24h Cytotox measuring activity
652289Quorum LuxO: Assay for inducers of light production in the absence of autoinducers using BH1651 (luxOD47E) Measured in Microorganism System Using Plate Reader - 2132-03_Inhibitor_Dose_DryPowder_Activityconfirmatory 54 drypowder compounds at dose in 03 Quorum LuxO: BH1651 measuring activity
652219Quorum LuxO: Assay for change of GFP production in the absence of autoinducers using SL353 (luxOD47E, qrr4-gp) Measured in Microorganism System Using Plate Reader - 2132-06_Inhibitor_Dose_DryPowder_Activityconfirmatory 15 drypowder compounds at dose in 06 Quorum LuxO: SLS353 measuring activity
652239Cholera Quorum: HTS for inducers of light production in the absence of autoinducers using BH1578 (luxS deficient, cqsA deficient) Measured in Microorganism System Using Plate Reader - 2132-01_Inhibitor_Dose_DryPowder_Activityconfirmatory 97 drypowder compounds at dose in 01 Cholera Quorum HTS measuring activity
588436Cholera Quorum: HTS for inducers of light production in the absence ofautoinducers using BH1578 (luxS deficient, cqsA deficient) Measured in Microorganism System Using Plate Reader - 2132-01_Agonist_SinglePoint_HTS_Activityscreening 350317 hts compounds at singlepoint in 01 Cholera Quorum HTS measuring activity
602243Cholera Quorum: HTS for inducers of light production in the absence of autoinducers using BH1578 (luxS deficient, cqsA deficient) Measured in Microorganism System Using Plate Reader - 2132-01_Agonist_Dose_CherryPick_Activityconfirmatory 623 cherrypick compounds at dose in 01 Cholera Quorum HTS measuring activity
686942Quorum LuxO: Assay for change of GFP production in the absence of autoinducers using SL353 (luxOD47E, qrr4-gp) Measured in Microorganism System Using Plate Reader - 2132-06_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory
588521Broad Institute Quorum Sensing in Vibrio cholera: CqsS/LuxQ Agonist Probe Projectsummary1
624140Cytotoxicity at 24 hours in dose with HeLa cells Measured in Cell-Based System Using Plate Reader - 2132-02_Agonist_Dose_DryPowder_Activityconfirmatory
624254Quorum LuxO: Assay for inducers of light production in the absence of#autoinducers using BH1651 (luxOD47E) Measured in Microorganism System Using Plate Reader - 2132-03_Agonist_Dose_CherryPick_Activityconfirmatory
624269Quorum LuxO: Assay for inducers of light production in the absence of#autoinducers using BH1651 (luxOD47E) Measured in Microorganism System Using Plate Reader - 2132-03_Agonist_Dose_DryPowder_Activityconfirmatory
651847Quorum LuxO: Assay for inducers of light production in the absence of autoinducers using BH1651 (luxOD47E) Measured in Microorganism System Using Plate Reader - 2132-03_Agonist_Dose_DryPowder_Activity_Set3confirmatory
651864Cytotoxicity at 24 hours in dose with HeLa cells Measured in Cell-Based System Using Plate Reader - 2132-02_Agonist_Dose_DryPowder_Activity_Set3confirmatory
Description:
Biological Relevance:
Quorum sensing is a process of bacterial cell-cell communication that relies upon
the production, release, detection, and response to extracellular signaling molecules called autoinducers. Quorum sensing allows bacteria to synchronously alter behavior in response to changes in the population density and species composition of the vicinal bacterial community. Quorum sensing controls collective behaviors including bioluminescence, sporulation, virulence factor production, and biofilm formation. Vibrio cholerae is the etiological agent of the disease cholera and its life cycle consists of alternating between human hosts and the aquatic environment. In V. cholerae, quorum sensing represses biofilm formation and virulence factor production and it activates protease production.

Project Goal:
The long-term goal of this research is to explore the molecular mechanisms that bacteria use for cell-cell communication (i.e., quorum sensing). Until recently, the ability of bacteria to communicate was considered an anomaly that occurred only in a few marine Vibrio species. It is now clear that cell-cell communication is the norm in the bacterial world and that understanding this process is fundamental to all of microbiology, including industrial and clinical microbiology. Here we propose to collaborate with the MLPCN to carry out a high-throughput screen to identify small molecules that modulate quorum-sensing in the human pathogen Vibrio cholerae. Follow up studies to further characterize the lead compounds identified in the screens will combine synthetic organic chemistry, bacterial genetics, biochemistry, and X-ray crystallography. Quorum-sensing
modulators identified through this work will provide lead compounds for the development of antibacterial drugs designed to interfere with quorum sensing which could have enormous ramifications for improving human health.

Our aim is to discover a probe that will inhibit LuxO. LuxO, the response regulator that functions to integrate the CAI-1 and AI-2 signals in the Vibrio cholerae quorum-sensing circuit, is a canonical sigma54 binding transcriptional activator that relies on ATP hydrolysis to promote open complex formation. Hundreds of highly conserved LuxO-homologs exist in bacteria and are currently under study. To our knowledge, there is only one chemical probe that modulates the activity of a LuxO-type response regulator, azaU. Our discovery of other probes will benefit the many scientists who study two-component signal transduction pathways; the most ubiquitous type of signaling systems found in bacteria.
Additional Information
Grant Number: R03 MH094166-01

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