{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:21:07Z","timestamp":1792185667616,"version":"4.4.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"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":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n                    must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n                    intracellular replication and growth\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n                    with ethoxzolamide recapitulates\n                    <jats:italic>phoPR<\/jats:italic>\n                    mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n                    growth in both macrophages and infected mice. Ethoxzolamide inhibits\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. tuberculosis<\/jats:named-content>\n                    carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence.\n                  <\/jats:p>","DOI":"10.1128\/aac.00719-15","type":"journal-article","created":{"date-parts":[[2015,5,18]],"date-time":"2015-05-18T22:31:37Z","timestamp":1431988297000},"page":"4436-4445","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":134,"title":["The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence"],"prefix":"10.1128","volume":"59","author":[{"given":"Benjamin K.","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Colvin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Needle","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Mba Medie","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A. DiGiuseppe","family":"Champion","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B.","family":"Abramovitch","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00305-09"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2007.09.006"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05102.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003496"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07601.x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2001.02500.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2006.03.017"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3013"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002767"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160354"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00403-13"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1116739"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507488102"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003282"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12688"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2450-9_20"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(88)90391-0"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06801.x"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2235593100"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02153-14"},{"key":"e_1_3_3_23_2","doi-asserted-by":"crossref","first-page":"6649","DOI":"10.1016\/j.bmcl.2009.10.009","article-title":"Carbonic anhydrase inhibitors. 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