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{"title"=>"Broad spectrum pro-quorum-sensing molecules as inhibitors of virulence in vibrios", "type"=>"journal", "authors"=>[{"first_name"=>"Wai Leung", "last_name"=>"Ng", "scopus_author_id"=>"7401613524"}, {"first_name"=>"Lark", "last_name"=>"Perez", "scopus_author_id"=>"36086577100"}, {"first_name"=>"Jianping", "last_name"=>"Cong", "scopus_author_id"=>"7102006867"}, {"first_name"=>"Martin F.", "last_name"=>"Semmelhack", "scopus_author_id"=>"7003888105"}, {"first_name"=>"Bonnie L.", "last_name"=>"Bassler", "scopus_author_id"=>"7003556315"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"issn"=>"15537366", "scopus"=>"2-s2.0-84864051841", "sgr"=>"84864051841", "pui"=>"365284258", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "pmid"=>"22761573", "doi"=>"10.1371/journal.ppat.1002767"}, "id"=>"faba0294-c5d2-3c78-b21b-94f87cbb0c6c", "abstract"=>"Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. Vibrio cholerae, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in V. cholerae have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate V. cholerae QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global V. cholerae QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in Vibrio species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.", "link"=>"http://www.mendeley.com/research/broad-spectrum-proquorumsensing-molecules-inhibitors-virulence-vibrios", "reader_count"=>119, "reader_count_by_academic_status"=>{"Unspecified"=>7, "Professor > Associate Professor"=>7, "Student > Doctoral Student"=>9, "Researcher"=>24, "Student > Ph. D. Student"=>34, "Student > Postgraduate"=>4, "Student > Master"=>10, "Other"=>1, "Student > Bachelor"=>18, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>7, "Professor > Associate Professor"=>7, "Student > Doctoral Student"=>9, "Researcher"=>24, "Student > Ph. D. Student"=>34, "Student > Postgraduate"=>4, "Student > Master"=>10, "Other"=>1, "Student > Bachelor"=>18, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Engineering"=>3, "Unspecified"=>8, "Biochemistry, Genetics and Molecular Biology"=>13, "Agricultural and Biological Sciences"=>69, "Medicine and Dentistry"=>1, "Neuroscience"=>1, "Chemistry"=>16, "Immunology and Microbiology"=>8}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>3}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>16}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>8}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>69}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>13}, "Unspecified"=>{"Unspecified"=>8}}, "reader_count_by_country"=>{"United States"=>4, "United Kingdom"=>1, "Italy"=>1, "India"=>1}, "group_count"=>4}

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• {"files"=>["https://ndownloader.figshare.com/files/321141", "https://ndownloader.figshare.com/files/321165", "https://ndownloader.figshare.com/files/321189", "https://ndownloader.figshare.com/files/321208", "https://ndownloader.figshare.com/files/321239", "https://ndownloader.figshare.com/files/321260", "https://ndownloader.figshare.com/files/321288", "https://ndownloader.figshare.com/files/321350"], "description"=>"<div><p>Quorum sensing (QS) is a bacterial cell-cell communication process that relies on the production and detection of extracellular signal molecules called autoinducers. QS allows bacteria to perform collective activities. <em>Vibrio cholerae</em>, a pathogen that causes an acute disease, uses QS to repress virulence factor production and biofilm formation. Thus, molecules that activate QS in <em>V. cholerae</em> have the potential to control pathogenicity in this globally important bacterium. Using a whole-cell high-throughput screen, we identified eleven molecules that activate <em>V. cholerae</em> QS: eight molecules are receptor agonists and three molecules are antagonists of LuxO, the central NtrC-type response regulator that controls the global <em>V. cholerae</em> QS cascade. The LuxO inhibitors act by an uncompetitive mechanism by binding to the pre-formed LuxO-ATP complex to inhibit ATP hydrolysis. Genetic analyses suggest that the inhibitors bind in close proximity to the Walker B motif. The inhibitors display broad-spectrum capability in activation of QS in <em>Vibrio</em> species that employ LuxO. To the best of our knowledge, these are the first molecules identified that inhibit the ATPase activity of a NtrC-type response regulator. Our discovery supports the idea that exploiting pro-QS molecules is a promising strategy for the development of novel anti-infectives.</p> </div>", "links"=>[], "tags"=>["pro-quorum-sensing", "molecules", "inhibitors", "virulence", "vibrios"], "article_id"=>123387, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002767.s001", "https://dx.doi.org/10.1371/journal.ppat.1002767.s002", "https://dx.doi.org/10.1371/journal.ppat.1002767.s003", "https://dx.doi.org/10.1371/journal.ppat.1002767.s004", "https://dx.doi.org/10.1371/journal.ppat.1002767.s005", "https://dx.doi.org/10.1371/journal.ppat.1002767.s006", "https://dx.doi.org/10.1371/journal.ppat.1002767.s007", "https://dx.doi.org/10.1371/journal.ppat.1002767.s008"], "stats"=>{"downloads"=>9, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Broad_Spectrum_Pro_Quorum_Sensing_Molecules_as_Inhibitors_of_Virulence_in_Vibrios/123387", "title"=>"Broad Spectrum Pro-Quorum-Sensing Molecules as Inhibitors of Virulence in Vibrios", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-06-28 00:56:27"}
• {"files"=>["https://ndownloader.figshare.com/files/617107"], "description"=>"<p>The CqsA/CqsS signal transduction system is shown as the example for the <i>V. cholerae</i> QS circuit. (Left) At low cell density (LCD), the CAI-1 autoinducer concentration is below the detection threshold, and the membrane bound CqsS receptor functions as a kinase. The LuxO response regulator is phosphorylated and it activates the transcription of genes encoding the four Qrr sRNA genes. Aided by the RNA chaperone Hfq, the Qrr sRNAs activate and repress translation of the AphA and HapR proteins, respectively. (Right) At high cell density (HCD), binding of CAI-1 to CqsS inhibits its kinase activity. LuxO is not phosphorylated and transcription of the <i>qrr</i> genes is terminated. Translation of AphA is inhibited and HapR is derepressed. Hundreds of genes are controlled by AphA and HapR, including genes required for biofilm formation and virulence. HapR also functions as a transcriptional activator of the heterologous <i>V. harveyi lux</i> operon <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002767#ppat.1002767-Miller1\" target=\"_blank\">[22]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002767#ppat.1002767-Rutherford1\" target=\"_blank\">[24]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002767#ppat.1002767-Hammer1\" target=\"_blank\">[26]</a>–<a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002767#ppat.1002767-Zhu2\" target=\"_blank\">[30]</a>. Dotted lines denote components that are not expressed while solid lines represent those that are produced.</p>", "links"=>[], "tags"=>["quorum-sensing", "circuit"], "article_id"=>287596, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_Quorum_Sensing_Circuit_in_Vibrio_cholerae_/287596", "title"=>"The Quorum-Sensing Circuit in <i>Vibrio cholerae</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:06:36"}
• {"files"=>["https://ndownloader.figshare.com/files/617192"], "description"=>"<p>(A) Chemical structures of the eleven QS-activating compounds. The structure of CAI-1 is shown for reference. (B) Differential responses to Class 1 and Class 2 compounds by the <i>V. cholerae</i> Δ<i>cqsA</i> Δ<i>luxS</i> double synthase mutant (BH1578) and the <i>luxO</i>^D47E mutant (BH1651). The normalized light (RLU, relative light units) produced was monitored in the absence (white) and presence of Class 1 (gray) or Class 2 (black) compounds. A representative experiment is shown using compound 1 (Class 1) and compound 11 (Class 2) from (A). (C) QS dose-response curves of <i>V. cholerae</i>. The normalized light (RLU, relative light units) produced by the <i>V. cholerae</i> Δ<i>cqsA</i> Δ<i>luxS</i> mutant carrying the <i>lux</i> operon (BH1578) is plotted as a function of the concentration of the eleven QS-activating compounds shown in (A). Black curves denote responses to Class 1 compounds. Blue curves denote responses to Class 2 compounds. The red curve denotes the response to the native autoinducer CAI-1, which is the positive control. Error bars are present, but are too small to be observed in the plot. The bars represent standard errors of the mean for three independent trials. (D) Effect of compound 11 on expression of <i>qrr</i>4. Expression of <i>qrr</i>4 was monitored in a <i>V. cholerae luxO</i>^D47E strain carrying a <i>qrr</i>4-<i>gfp</i> transcriptional reporter (SLS353). The response is shown in the presence and absence of 50 µM compound 11. Expression of <i>qrr</i>4-<i>gfp</i> from the Δ<i>luxO</i> mutant (SLS373) is shown for reference. AU denotes arbitrary units. Error bars represent standard errors of the mean for three independent trials.</p>", "links"=>[], "tags"=>["qs-activating", "compounds"], "article_id"=>287682, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_QS_activating_compounds_in_V_cholerae_/287682", "title"=>"Identification of QS-activating compounds in <i>V. cholerae</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:08:02"}
• {"files"=>["https://ndownloader.figshare.com/files/617495"], "description"=>"<p>(A) Michaelis-Menton enzyme kinetic analysis of LuxO ATPase activity. The LuxO D47E ATP hydrolysis rate is plotted as a function of the concentration of ATP in the presence of the indicated amounts of compound 11. Error bars represent standard errors of the mean for at least three independent trials. (B) Lineweaver-Burk plot derived from the assay described in (A). (C) Lineweaver-Burk plot derived from a LuxO D47E ATPase assay in the presence of the indicated amounts of compound 12. (D) Correlation between % inhibition of LuxO D47E ATPase activity (2.5 mM ATP and 30 µM inhibitors) and EC₅₀ of QS-activation potency (derived from <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002767#ppat-1002767-g003\" target=\"_blank\">Figure 3</a>) for the different LuxO inhibitors.</p>", "links"=>[], "tags"=>["kinetic", "analyses", "luxo", "atpase"], "article_id"=>287982, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g005", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enzyme_kinetic_analyses_of_LuxO_ATPase_inhibition_/287982", "title"=>"Enzyme kinetic analyses of LuxO ATPase inhibition.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:13:02"}
• {"files"=>["https://ndownloader.figshare.com/files/617676"], "description"=>"<p>(A) Normalized light (RLU, relative light units) produced by the <i>V. harveyi luxO</i>^D47E strain in the absence and presence of 50 µM of compounds 11 and 12. (B) Colony morphology of the constitutively active <i>V. parahaemolyticus luxO^*</i> mutant (LM4476) and the isogenic <i>V. parahaemolyticus</i> Δ<i>luxO</i> mutant (LM9688) in the absence and presence of 500 µM compounds 11 and 12. Each strain was inoculated four times on the same plate.</p>", "links"=>[], "tags"=>["luxo", "inhibitors", "activate", "qs", "vibiro"], "article_id"=>288162, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g007", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_LuxO_inhibitors_activate_QS_in_different_Vibiro_species_/288162", "title"=>"The LuxO inhibitors activate QS in different Vibiro species.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:16:02"}
• {"files"=>["https://ndownloader.figshare.com/files/617747"], "description"=>"<p>(A) Western blot analysis of TcpA (Top), HapR (middle), and LuxS (bottom, loading control) in a <i>V. cholerae luxO</i>^D47E mutant in the presence of 0, 12.5, 25, 50, 100, and 200 µM compound 12. (B) Western blot analysis of the cytoplasmic and secreted VopD in the <i>V. parahaemolyticus</i> constitutively active <i>luxO^*</i> strain (LM4476) in the presence of 0, 200, and 500 µM compound 12. An isogenic <i>V. parahaemolyticus</i> Δ<i>luxO</i> mutant (LM9968) is included as the control. (C) Cytotoxicity of <i>V. parahaemolyticus</i> LM4476 (<i>luxO</i>^*) on cultured HeLa cells in the absence and presence of 500 µM compound 12. Cytotoxicity was measured by lactate dehydrogenase (LDH) release from HeLa cells. 100% cytotoxicity denotes LDH activity released upon treatment with 0.45% (v/v) Triton-X100. The <i>V. parahaemolyticus</i> Δ<i>luxO</i> mutant LM9968 and the no-bacteria control are included for comparison. Error bars represent standard errors of the mean for three independent trials.</p>", "links"=>[], "tags"=>["virulence", "luxo"], "article_id"=>288247, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g008", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Control_of_virulence_factor_production_by_LuxO_inhibitors_/288247", "title"=>"Control of virulence factor production by LuxO inhibitors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:17:27"}
• {"files"=>["https://ndownloader.figshare.com/files/617419"], "description"=>"<p>LuxO D47E DNA binding in the presence and absence of compounds 11 and 12 was investigated by gel mobility shift assays (A) and fluorescent anisotropy assays (B). In (A), LuxO D47E was present at 1 µM. Compounds 11 and 12 were present at 200 µM. In (B), LuxO D47E was present at the indicated concentrations and compounds 11 and 12 were present at 200 µM. Error bars are present, but are too small to be observed in the plot. The bars represent standard errors of the mean for three independent trials.</p>", "links"=>[], "tags"=>["luxo", "inhibitor", "dna"], "article_id"=>287909, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g004", "stats"=>{"downloads"=>3, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_LuxO_Inhibitor_does_not_affect_DNA_binding_/287909", "title"=>"The LuxO Inhibitor does not affect DNA binding.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:11:49"}
• {"files"=>["https://ndownloader.figshare.com/files/617564"], "description"=>"<p>(A) Normalized light (RLU, relative light units) produced by the <i>V. cholerae</i> Δ<i>luxO</i> strain carrying <i>luxO</i>^D47E and <i>luxO</i>^D47E harboring additional mutations in the absence (white) or presence of 100 µM of compound 11 (black) or compound 12 (gray). Error bars represent standard errors of the mean for three independent trials. Western blot analyses demonstrate that the wild type and all mutants produce comparable amounts of LuxO protein. (B) The locations of the resistance-conferring mutations are inferred from the ATP-bound <i>Aquifex aeolicus</i> NtrC1 structure (3M0E). Two monomers of NtrC1 are shown (cyan and green). The residues predicted to form the Walker B motif are shown in blue. The four resistance-conferring mutations (I211, L215, L242, and V294) are shown in orange. The catalytic arginine residue and ATP are shown in magenta (with side chain) and yellow, respectively.</p>", "links"=>[], "tags"=>["luxo", "mutants", "resistant"], "article_id"=>288051, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g006", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Isolation_of_LuxO_mutants_resistant_to_inhibition_/288051", "title"=>"Isolation of LuxO mutants resistant to inhibition.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:14:11"}
• {"files"=>["https://ndownloader.figshare.com/files/617331"], "description"=>"<p>The core chemical structure of the LuxO inhibitors is shown at the top. All analogs possess the identical 6-thio-5-azauracil moiety with modifications in the terminal side chains (denoted R). Variations in the side chain are shown on the right. Normalized light (RLU, relative light units) produced by the <i>V. cholerae luxO</i>^D47E strain (BH1651) carrying the <i>lux</i> operon is plotted as a function of concentration of the eight different analogs. Error bars are present, but are too small to be observed in the plot. The bars represent standard errors of the mean for three independent trials.</p>", "links"=>[], "tags"=>["luxo"], "article_id"=>287826, "categories"=>["Biochemistry", "Chemistry"], "users"=>["Wai-Leung Ng", "Lark Perez", "Jianping Cong", "Martin F. Semmelhack", "Bonnie L. Bassler"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002767.g003", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structure_Activity_Relationship_of_LuxO_inhibitors_/287826", "title"=>"Structure-Activity-Relationship of LuxO inhibitors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-06-28 02:10:26"}

PMC Usage Stats | Further Information

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Relative Metric

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F1000Prime