{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:10:50Z","timestamp":1791277850187,"version":"4.1.0"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2013,4,1]],"date-time":"2013-04-01T00:00:00Z","timestamp":1364774400000},"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":[[2013,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Since the discovery of streptomycin's bactericidal activity against\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            , aminoglycosides have been utilized to treat tuberculosis (TB). Today, the aminoglycosides kanamycin and amikacin are used to treat multidrug-resistant (MDR) TB, and resistance to any of the second-line injectable antibiotics, including kanamycin, amikacin, or capreomycin, is a defining characteristic of extensively drug-resistant (XDR) TB. Resistance to kanamycin and streptomycin is thought to be due to the acquisition of unlinked chromosomal mutations. However, we identified eight independent mutations in the 5\u2032 untranslated region of the transcriptional activator\n            <jats:italic>whiB7<\/jats:italic>\n            that confer low-level resistance to both aminoglycosides. The mutations lead to 23- to 145-fold increases in\n            <jats:italic>whiB7<\/jats:italic>\n            transcripts and subsequent increased expression of both\n            <jats:italic>eis<\/jats:italic>\n            (\n            <jats:italic>Rv2416c<\/jats:italic>\n            ) and\n            <jats:italic>tap<\/jats:italic>\n            (\n            <jats:italic>Rv1258c<\/jats:italic>\n            ). Increased expression of\n            <jats:italic>eis<\/jats:italic>\n            confers kanamycin resistance in these mutants, while increased expression of\n            <jats:italic>tap<\/jats:italic>\n            , which encodes an efflux pump, is a previously uncharacterized mechanism of low-level streptomycin resistance. Additionally, high-level resistance to streptomycin arose at a much higher frequency in\n            <jats:italic>whiB7<\/jats:italic>\n            mutants than in a wild-type (WT) strain. Although\n            <jats:italic>whiB7<\/jats:italic>\n            is typically associated with intrinsic antibiotic resistance in\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            , these data suggest that mutations in an uncharacterized regulatory region of\n            <jats:italic>whiB7<\/jats:italic>\n            contribute to cross-resistance against clinically used second-line antibiotics. As drug resistance continues to develop and spread, understanding the mechanisms and molecular basis of antibiotic resistance is critical for the development of rapid molecular tests to diagnose drug-resistant TB strains and ultimately for designing regimens to treat drug-resistant cases of TB.\n          <\/jats:p>","DOI":"10.1128\/aac.02191-12","type":"journal-article","created":{"date-parts":[[2013,2,5]],"date-time":"2013-02-05T04:56:57Z","timestamp":1360040217000},"page":"1857-1865","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":140,"title":["Aminoglycoside Cross-Resistance in Mycobacterium tuberculosis Due to Mutations in the 5\u2032 Untranslated Region of\n            <i>whiB7<\/i>"],"prefix":"10.1128","volume":"57","author":[{"given":"Analise Z.","family":"Reeves","sequence":"first","affiliation":[{"name":"Microbiology and Molecular Genetics Graduate Program, Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA"},{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia J.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Microbiology and Molecular Genetics Graduate Program, Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA"},{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razvan","family":"Sultana","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Boston University, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seidu","family":"Malik","sequence":"additional","affiliation":[{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie B.","family":"Plikaytis","sequence":"additional","affiliation":[{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Shinnick","sequence":"additional","affiliation":[{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"Posey","sequence":"additional","affiliation":[{"name":"Division of TB Elimination, National Center for HIV\/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Global tuberculosis control\u2014epidemiology, strategy, financing","author":"World Health Organization","year":"2009","unstructured":"World Health Organization. 2009. 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