{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T09:02:52Z","timestamp":1791018172249,"version":"4.1.0"},"reference-count":46,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2013,8,6]],"date-time":"2013-08-06T00:00:00Z","timestamp":1375747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2013,8,30]],"date-time":"2013-08-30T00:00:00Z","timestamp":1377820800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2013,8,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Vibrio cholerae<\/jats:named-content>\n            , a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            is tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and B\u02b9, representing two novel classes of\n            <jats:italic>toxT<\/jats:italic>\n            transcription inhibitors. All three compounds reduce production of both CT and the toxin-coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of the\n            <jats:italic>toxT<\/jats:italic>\n            promoter and that toxtazins B and B\u02b9 work at the level of the\n            <jats:italic>tcpP<\/jats:italic>\n            promoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            caused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, as\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            is transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade in\n            <jats:named-content content-type=\"genus-species\">V. cholerae<\/jats:named-content>\n            , toxtazin A and toxtazins B and B\u02b9. We demonstrate that (i) small-molecule inhibitors of virulence gene production can be identified in a high-throughput screen, (ii) targeting virulence gene production is an effective therapeutic strategy, and (iii) small-molecule inhibitors can uncover unknown layers of gene regulation, even in well-studied regulatory cascades.\n          <\/jats:p>","DOI":"10.1128\/mbio.00403-13","type":"journal-article","created":{"date-parts":[[2013,8,7]],"date-time":"2013-08-07T05:22:44Z","timestamp":1375852964000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":46,"title":["Small-Molecule Inhibitors of\n            <i>toxT<\/i>\n            Expression in Vibrio cholerae"],"prefix":"10.1128","volume":"4","author":[{"given":"Rebecca","family":"Anthouard","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan, Medical School, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor J.","family":"DiRita","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Michigan, Medical School, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.8.3733-3739.1999"},{"key":"e_1_3_2_3_2","first-page":"153","article-title":"Cholera toxin\u2014a foe & a friend","volume":"133","author":"Sanchez J","year":"2011","unstructured":"SanchezJ HolmgrenJ . 2011. Cholera toxin\u2014a foe & a friend. Indian J. Med. Res. 133:153\u2013163.","journal-title":"Indian J. Med. Res."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.9.2833"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.12.5403"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.02111.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1999.01215.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.181.14.4250-4256.1999"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014640108"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1086\/376619"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196807252790402"},{"key":"e_1_3_2_12_2","volume-title":"Cholera: its nature, symptoms, and treatment","author":"Ayre J","year":"1849","unstructured":"AyreJ . 1849. 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