{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:04:13Z","timestamp":1792105453799,"version":"4.4.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"27","license":[{"start":{"date-parts":[[2019,12,19]],"date-time":"2019-12-19T00:00:00Z","timestamp":1576713600000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI099394"],"award-info":[{"award-number":["R01AI099394"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI105129"],"award-info":[{"award-number":["R01AI105129"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI103268"],"award-info":[{"award-number":["R01AI103268"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI119145"],"award-info":[{"award-number":["R01AI119145"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI007180"],"award-info":[{"award-number":["T32AI007180"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,7,2]]},"abstract":"<jats:p>\n                    The pathogen\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    colonizes and infects a variety of different sites within the human body. To adapt to these different environments,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    relies on a complex and finely tuned regulatory network. While some of these networks have been well-elucidated, the functions of more than 50% of the transcriptional regulators in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    remain unexplored. Here, we assess the contribution of the LacI family of metabolic regulators to staphylococcal virulence. We found that inactivating the purine biosynthesis regulator\n                    <jats:italic>purR<\/jats:italic>\n                    resulted in a strain that was acutely virulent in bloodstream infection models in mice and in ex vivo models using primary human neutrophils. Remarkably, these enhanced pathogenic traits are independent of purine biosynthesis, as the\n                    <jats:italic>purR<\/jats:italic>\n                    mutant was still highly virulent in the presence of mutations that disrupt PurR\u2019s canonical role. Through the use of transcriptomics coupled with proteomics, we revealed that a number of virulence factors are differentially regulated in the absence of\n                    <jats:italic>purR<\/jats:italic>\n                    . Indeed, we demonstrate that PurR directly binds to the promoters of genes encoding virulence factors and to master regulators of virulence. These results guided us into further ex vivo and in vivo studies, where we discovered that\n                    <jats:italic>S. aureus<\/jats:italic>\n                    toxins drive the death of human phagocytes and mice, whereas the surface adhesin FnbA contributes to the increased bacterial burden observed in the\n                    <jats:italic>purR<\/jats:italic>\n                    mutant. Thus,\n                    <jats:italic>S. aureus<\/jats:italic>\n                    repurposes a metabolic regulator to directly control the expression of virulence factors, and by doing so, tempers its pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1904280116","type":"journal-article","created":{"date-parts":[[2019,6,19]],"date-time":"2019-06-19T19:25:12Z","timestamp":1560972312000},"page":"13563-13572","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":88,"title":["The purine biosynthesis regulator PurR moonlights as a virulence regulator in\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1073","volume":"116","author":[{"given":"William E.","family":"Sause","sequence":"first","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irnov","family":"Irnov","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Copin","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"},{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell J.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Sommerfield","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avantika","family":"Dhabaria","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory, New York University School of Medicine, New York, NY 10016;"},{"name":"Division of Advanced Research, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manor","family":"Askenazi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;"},{"name":"Biomedical Hosting LLC, Arlington, MA 02474;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrix","family":"Ueberheide","sequence":"additional","affiliation":[{"name":"Proteomics Laboratory, New York University School of Medicine, New York, NY 10016;"},{"name":"Division of Advanced Research, New York University School of Medicine, New York, NY 10016;"},{"name":"Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Shopsin","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"},{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harm","family":"van Bakel","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;"},{"name":"Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor J.","family":"Torres","sequence":"additional","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, NY 10016;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,6,19]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJM199808203390806","article-title":"Staphylococcus aureus infections","volume":"339","author":"Lowy F. 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J. Torres, Staphylococcus aureus pathogenesis in diverse host environments. Pathog. Dis. 75, ftx005 (2017).","journal-title":"Pathog. Dis."},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrmicro3521","article-title":"Staphylococcal manipulation of host immune responses","volume":"13","author":"Thammavongsa V.","year":"2015","unstructured":"V. Thammavongsa, H. K. Kim, D. Missiakas, O. Schneewind, Staphylococcal manipulation of host immune responses. Nat. Rev. Microbiol. 13, 529\u2013543 (2015).","journal-title":"Nat. Rev. Microbiol."},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1146\/annurev.genet.42.110807.091640","article-title":"Quorum sensing in staphylococci","volume":"42","author":"Novick R. P.","year":"2008","unstructured":"R. P. Novick, E. Geisinger, Quorum sensing in staphylococci. Annu. Rev. Genet. 42, 541\u2013564 (2008).","journal-title":"Annu. Rev. 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Cell Biol."},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1128\/JB.182.11.3197-3203.2000","article-title":"Identification, cloning, and initial characterization of rot, a locus encoding a regulator of virulence factor expression in Staphylococcus aureus","volume":"182","author":"McNamara P. J.","year":"2000","unstructured":"P. J. McNamara, K. C. Milligan-Monroe, S. Khalili, R. A. Proctor, Identification, cloning, and initial characterization of rot, a locus encoding a regulator of virulence factor expression in Staphylococcus aureus. J. Bacteriol. 182, 3197\u20133203 (2000).","journal-title":"J. Bacteriol."},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/1471-2164-14-126","article-title":"Global analysis of transcriptional regulators in Staphylococcus aureus","volume":"14","author":"Ibarra J. A.","year":"2013","unstructured":"J. A. Ibarra, E. P\u00e9rez-Rueda, R. K. Carroll, L. N. Shaw, Global analysis of transcriptional regulators in Staphylococcus aureus. BMC Genomics 14, 126 (2013).","journal-title":"BMC Genomics"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"11366","DOI":"10.1074\/jbc.M513015200","article-title":"The structure of CodY, a GTP- and isoleucine-responsive regulator of stationary phase and virulence in gram-positive bacteria","volume":"281","author":"Levdikov V. M.","year":"2006","unstructured":"V. M. Levdikov, E. Blagova, P. Joseph, A. L. Sonenshein, A. J. Wilkinson, The structure of CodY, a GTP- and isoleucine-responsive regulator of stationary phase and virulence in gram-positive bacteria. J. Biol. Chem. 281, 11366\u201311373 (2006).","journal-title":"J. Biol. Chem."},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1128\/JB.01545-07","article-title":"Staphylococcus aureus CodY negatively regulates virulence gene expression","volume":"190","author":"Majerczyk C. 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Ying, Regulation of alpha- and beta-hemolysins by the sar locus of Staphylococcus aureus. J. Bacteriol. 176, 580\u2013585 (1994).","journal-title":"J. Bacteriol."},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1046\/j.1365-2958.1998.01126.x","article-title":"SarA level is a determinant of agr activation in Staphylococcus aureus","volume":"30","author":"Chien Y.","year":"1998","unstructured":"Y. Chien, A. C. Manna, A. L. Cheung, SarA level is a determinant of agr activation in Staphylococcus aureus. Mol. Microbiol. 30, 991\u20131001 (1998).","journal-title":"Mol. Microbiol."},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1128\/JB.01517-10","article-title":"Defining the strain-dependent impact of the staphylococcal accessory regulator (sarA) on the alpha-toxin phenotype of Staphylococcus aureus","volume":"193","author":"Zielinska A. K.","year":"2011","unstructured":"A. K. 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Noble, FIMO: Scanning for occurrences of a given motif. Bioinformatics 27, 1017\u20131018 (2011).","journal-title":"Bioinformatics"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"e10146","DOI":"10.1371\/journal.pone.0010146","article-title":"Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation","volume":"5","author":"Boles B. R.","year":"2010","unstructured":"B. R. Boles, M. Thoendel, A. J. Roth, A. R. Horswill, Identification of genes involved in polysaccharide-independent Staphylococcus aureus biofilm formation. PLoS One 5, e10146 (2010).","journal-title":"PLoS One"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41467-017-02448-6","article-title":"Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314","volume":"9","author":"Blake K. J.","year":"2018","unstructured":"K. J. Blake ., Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat. Commun. 9, 37 (2018).","journal-title":"Nat. Commun."},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1038\/nm.2451","article-title":"A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice","volume":"17","author":"Inoshima I.","year":"2011","unstructured":"I. Inoshima ., A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med. 17, 1310\u20131314 (2011).","journal-title":"Nat. Med."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.chom.2015.05.011","article-title":"Synergistic action of Staphylococcus aureus \u03b1-toxin on platelets and myeloid lineage cells contributes to lethal sepsis","volume":"17","author":"Powers M. E.","year":"2015","unstructured":"M. E. Powers, R. E. 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