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BioAssay: AID 2106

Broad Institute MLPCN Quorum Sensing Project

density, is used by bacteria to regulate a variety of physiological functions. While universal signaling themes exist, variations in the design of the extracellular signals, the signal detection apparatuses, and the biochemical mechanisms of signal relay have allowed quorum-sensing systems to be exquisitely adapted for their varied uses. Until quite recently, the universe of quorum-sensing more ..
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AID: 2106
Data Source: Broad Institute (2035-01_Modulators)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-11-05
Modify Date: 2011-02-22
Targets
Depositor Specified Assays
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AIDNameTypeComment
2094Plate Read Microorganism-Based Primary HTS to Identify Modulators of the AI-2 Quorum Sensing Systemscreening302266 hts compounds at singlepoint in JMH597 HTS Screen measuring activity set 1
2724Luminescence Microorganism-Based Dose Retest to Identify Modulators of the AI-2 Quorum Sensing Systemconfirmatory7 cherrypick compounds at dose in JMH597 HTS Screen measuring activity set 1
2725Absorbance Microorganism-Based Dose Retest to Identify Inhibitors of Vibrio harveyiconfirmatory7 cherrypick compounds at dose in JMH597 HTS Screen measuring viability set 1
2736Luminescence Microorganism-Based Retest to Identify Modulators of the AI-2 Quorum Sensing Systemscreening749 cherrypick compounds at singlepoint in JMH597 HTS Screen measuring activity set 1
2726Absorbance Microorganism-Based Retest to Identify Inhibitors of Vibrio harveyiscreening749 cherrypick compounds at singlepoint in JMH597 HTS Screen measuring viability set 1
2735Luminescence Microorganism Dose Retest to Identify Inhibitors of the AI-2 Quorum Sensing Systemconfirmatory7 cherrypick compounds at dose in BB721 Counter for downstream inhibitors measuring activity set 1
2723Absorbance Microorganism Dose Retest to Identify Inhibitors of Vibrio harveyiconfirmatory7 cherrypick compounds at dose in BB721 Counter for downstream inhibitors measuring viability set 1
2727Luminescence Microorganism Retest to Identify Inhibitors of the AI-2 Quorum Sensing Systemscreening749 cherrypick compounds at singlepoint in BB721 Counter for downstream inhibitors measuring activity set 1
2728Absorbance Microorganism-Based Retest to Identify Inhibitors of Vibrio harveyiscreening749 cherrypick compounds at singlepoint in BB721 Counter for downstream inhibitors measuring viability set 1
434943Absorbance Microorganism Dose Response to Identify Inhibitors of Vibrio harveyiconfirmatory7 cherrypick compounds at dose in MM32 Counter to ID LuxS inhibitors vs LuxPQ antagonists measuring viability set 1
434944Luminescence Cell-Free Homogeneous Dose Response to Identify Inhibitors of Lux-Sconfirmatory7 cherrypick compounds at dose in LuxS Enzymatic Assay measuring activity set 1
493063Quorum Sensing, LuxS, LuxPQ Measured in Microorganism System Using Plate Reader - 2035-01_Inhibitor_DoseNoFile_DryPowder_Activityconfirmatory21 drypowder compounds at dose in JMH597 HTS Screen measuring activity set 1
493072Quorum Sensing, LuxS, LuxPQ Measured in Microorganism System Using Plate Reader - 2035-01_Inhibitor_DoseNoFile_DryPowder_Activity_Set2confirmatory24 drypowder compounds at dose in JMH597 HTS Screen measuring activity set 2
493075Quorum Sensing, LuxS, LuxPQ Measured in Microorganism System Using Plate Reader - 2035-01_Inhibitor_DoseNoFile_DryPowder_Activity_Set3confirmatory26 drypowder compounds at dose in JMH597 HTS Screen measuring activity set 3
493096Quorum Sensing Measured in Microorganism System Using Plate Reader - 2035-02_Inhibitor_DoseNoFile_DryPowder_Activity_Set2confirmatory12 drypowder compounds at dose in BB721 Counter for downstream inhibitors measuring activity set 2
493101Quorum Sensing, LuxS, LuxPQ Measured in Microorganism System Using Plate Reader - 2035-01_Inhibitor_DoseNoFile_DryPowder_Activity_Set4confirmatory14 drypowder compounds at dose in JMH597 HTS Screen measuring activity set 4
493097Quorum Sensing Measured in Microorganism System Using Plate Reader - 2035-02_Inhibitor_DoseNoFile_DryPowder_Activity_Set4confirmatoryBB721 Counter for downstream inhibitors set 4
493103Quorum Sensing Measured in Microorganism System Using Plate Reader - 2035-02_Inhibitor_DoseNoFile_DryPowder_Activity_Set3confirmatory26 drypowder compounds at dose in BB721 Counter for downstream inhibitors measuring activity set 3
493104Quorum Sensing Measured in Microorganism System Using Plate Reader - 2035-02_Inhibitor_DoseNoFile_DryPowder_Activityconfirmatory7 drypowder compounds at dose in BB721 Counter for downstream inhibitors measuring activity set 1
493116Quorum Sensing LuxPQ Measured in Microorganism System Using Plate Reader - 2035-03_Inhibitor_Dose_DryPowder_Activity_Set4confirmatory14 drypowder compounds at dose in MM32 Counter to ID LuxS inhibitors vs LuxPQ antagonists measuring activity set 4
493117Quorum Sensing LuxPQ Measured in Microorganism System Using Plate Reader - 2035-03_Inhibitor_Dose_DryPowder_Activity_Set3confirmatory21 drypowder compounds at dose in MM32 Counter to ID LuxS inhibitors vs LuxPQ antagonists measuring activity set 3
493118Quorum Sensing LuxPQ Measured in Microorganism System Using Plate Reader - 2035-03_Inhibitor_Dose_DryPowder_Activityconfirmatory7 drypowder compounds at dose in MM32 Counter to ID LuxS inhibitors vs LuxPQ antagonists measuring activity set 1
493119Quorum Sensing LuxPQ Measured in Microorganism System Using Plate Reader - 2035-03_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory12 drypowder compounds at dose in MM32 Counter to ID LuxS inhibitors vs LuxPQ antagonists measuring activity set 2
493167LuxS Measured in Biochemical System Using Plate Reader - 2035-05_Inhibitor_Dose_DryPowder_Activity_Set3confirmatory11 drypowder compounds at dose in LuxS Enzymatic Assay measuring activity set 3
493172LuxS Measured in Biochemical System Using Plate Reader - 2035-05_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory12 drypowder compounds at dose in LuxS Enzymatic Assay measuring activity set 2
Description:
Primary Collaborators:
Bonnie L. Bassler, Princeton University,Princeton, New Jersey,bbassler@princeton.edu, 609-258-2857

Biological Relevance:
Quorum sensing, or the control of gene expression in response to cell
density, is used by bacteria to regulate a variety of physiological functions. While universal signaling themes exist, variations in the design of the extracellular signals, the signal detection apparatuses, and the biochemical mechanisms of signal relay have allowed quorum-sensing systems to be exquisitely adapted for their varied uses. Until quite recently, the universe of quorum-sensing autoinducers was assumed to be populated mainly by acyl-homoserine lactones (HSLs; used by Gram-negative bacteria)and processed view changed with our discovery that the bioluminescent marine bacterium Vibrio harveyi, and its pathogenic relative Vibrio cholerae, make and integrate information from multiple autoinducers. It is now generally acknowledged that many bacteria synthesize, detect, and integrate information from multiple autoinducers. The chemical lexicon continues to grow as new small molecules are identified that play roles in bacterial communication.
The processes controlled by quorum sensing are diverse and reflect
the specific needs of particular bacterial communities inhabiting unique niches. Molecules that modulate quorum sensing have potential use as anti-microbial drugs aimed at bacteria that use quorum sensing to control virulence. Similarly, the biosynthetic enzymes involved in autoinducer production and the autoinducer detection apparatuses are potential targets for novel anti-microbial drug design. The artificial manipulation of beneficial quorum-sensing processes could be used to improve industrial scale production of natural products such as antibiotics. Beyond the biotechnological and medical applications of this research, a continued study of quorum sensing promises to provide insight into novel mechanisms of intra- and intercellular signal transmission, intra- and inter-species communication, and the evolution of multicellularity.
Among quorum-sensing systems, the V. harveyi circuit is particularly well suited for study. First, all of the components of the network have been identified, in many cases purified, and in some cases structurally characterized. Second, the structures of the autoinducers have been determined, and in vitro procedures for their syntheses have been developed. Third, well established genetics and a variety of V. harveyi mutants are available in every single step of the signaling pathway, including nulls and constitutively signaling and non-signaling alleles of most components. Fourth, both bioluminescence and in vivo reporter-gene expression systems are well established in V. harveyi and enable real-time monitoring of quorum-sensing network function. Together, these advantages should allow us to develop, for the first time, potent quorum-sensing inhibitors. We can exploit these both for therapeutic purposes as well as for developing a full mechanistic understanding of the molecular events underlying signal integration in quorum sensing.

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). This project is an integrative chemical, structural, and biological study of a recently identified quorum-sensing circuit whose functioning depends on the production and detection of a small molecule signal called autoinducer-2 (AI-2). AI-2, unlike other known bacterial autoinducers, is a universal quorum-sensing signal that mediates communication among different bacterial species. We will carry out high-throughput screens to identify inhibitors of the AI-2 synthase, LuxS and the AI-2 receptor, LuxPQ. Follow up studies to further characterize the lead compounds identified from the screens will combine synthetic organic chemistry, bacterial genetics, biochemistry, and X-ray crystallography. Antagonists of the AI-2 signaling pathway identified through this work will provide lead compounds for the development of broad-spectrum antibacterial drugs designed to interfere with quorum sensing which could have enormous ramifications for bettering human health.

1)Probe attributes:
a.Probe that inhibits LuxS with an IC50 <200nM.
b.Probe that inhibits LuxPQ with an IC50 <200nM.

Keywords: Quorum -Sensing, LuxS, LuxPQ, Luminescence, anti-bacterial
Additional Information
Grant Number: 1 R03 MH086452-01

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