{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T07:57:25Z","timestamp":1762761445935,"version":"3.41.2"},"reference-count":40,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2017,11,22]],"date-time":"2017-11-22T00:00:00Z","timestamp":1511308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2017,12,1]],"date-time":"2017-12-01T00:00:00Z","timestamp":1512086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Africa Health Research Institute"},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["U19AI110818"],"award-info":[{"award-number":["U19AI110818"]}],"id":[{"id":"10.13039\/100000002","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":["U19AI110818"],"award-info":[{"award-number":["U19AI110818"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Genetics-based drug susceptibility testing has improved the diagnosis of drug-resistant tuberculosis but is limited by our lack of knowledge of all resistance mechanisms. Next-generation sequencing has assisted in identifying the principal genetic mechanisms of resistance for many drugs, but a significant proportion of phenotypic drug resistance is unexplained genetically. Few studies have formally compared the transcriptomes of susceptible and resistant\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            strains. We carried out comparative whole-genome transcriptomics of extensively drug-resistant (XDR) clinical isolates using RNA sequencing (RNA-seq) to find novel transcription-mediated mechanisms of resistance. We identified a promoter mutation (t to c) at position \u221211 (t\u221211c) relative to the start codon of\n            <jats:italic>ethA<\/jats:italic>\n            that reduces the expression of a monooxygenase (EthA) that activates ethionamide. (In this article, nucleotide changes are lowercase and amino acid substitutions are uppercase.) Using a flow cytometry-based reporter assay, we show that the reduced transcription of\n            <jats:italic>ethA<\/jats:italic>\n            is not due to transcriptional repression by\n            <jats:italic>ethR<\/jats:italic>\n            . Clinical strains harboring this mutation were resistant to ethionamide. Other\n            <jats:italic>ethA<\/jats:italic>\n            promoter mutations were identified in a global genomic survey of resistant\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            strains. These results demonstrate a new mechanism of ethionamide resistance that can cause high-level resistance when it is combined with other ethionamide resistance-conferring mutations. Our study revealed many other genes which were highly up- or downregulated in XDR strains, including a toxin-antitoxin module (\n            <jats:italic>mazF5 mazE5<\/jats:italic>\n            ) and tRNAs (\n            <jats:italic>leuX<\/jats:italic>\n            and\n            <jats:italic>thrU<\/jats:italic>\n            ). This suggests that global transcriptional modifications could contribute to resistance or the maintenance of bacterial fitness have also occurred in XDR strains.\n          <\/jats:p>","DOI":"10.1128\/aac.01461-17","type":"journal-article","created":{"date-parts":[[2017,10,10]],"date-time":"2017-10-10T00:50:18Z","timestamp":1507596618000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":28,"title":["Whole-Transcriptome and -Genome Analysis of Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolates Identifies Downregulation of\n            <i>ethA<\/i>\n            as a Mechanism of Ethionamide Resistance"],"prefix":"10.1128","volume":"61","author":[{"given":"Lynne","family":"de Welzen","sequence":"first","affiliation":[{"name":"Africa Health Research Institute (AHRI), School of Laboratory Medicine &amp; Medical Sciences, University of KwaZulu-Natal, KwaZulu-Natal, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vegard","family":"Eldholm","sequence":"additional","affiliation":[{"name":"Infectious Disease Control and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kashmeel","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Africa Health Research Institute (AHRI), School of Laboratory Medicine &amp; Medical Sciences, University of KwaZulu-Natal, KwaZulu-Natal, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abigail L.","family":"Manson","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashlee M.","family":"Earl","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander S.","family":"Pym","sequence":"additional","affiliation":[{"name":"Africa Health Research Institute (AHRI), School of Laboratory Medicine &amp; Medical Sciences, University of KwaZulu-Natal, KwaZulu-Natal, South Africa"},{"name":"University College London (UCL), London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001880"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1903.120998"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62675-6"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60438-8"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00521-07"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00081-09"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00486-15"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3548"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00062-6"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-015-0164-0"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2735"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MGM2-0036-2013"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s15010-004-3097-x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201011-1924OC"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/174.5.1085"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.540"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00110-08"},{"key":"e_1_3_3_19_2","first-page":"153","article-title":"Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Turkey","volume":"32","author":"Y\u00fcksel P","year":"2009","unstructured":"Y\u00fcksel P Tansel\u00d6. 2009. Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Turkey. 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Afr J Clin Exp Microbiol10:64\u201379.","journal-title":"Afr J Clin Exp Microbiol"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1611283113"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth996"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01461-17","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01461-17","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:49:24Z","timestamp":1645476564000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01461-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12]]},"references-count":40,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,12]]}},"alternative-id":["10.1128\/AAC.01461-17"],"URL":"https:\/\/doi.org\/10.1128\/aac.01461-17","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"type":"print","value":"0066-4804"},{"type":"electronic","value":"1098-6596"}],"subject":[],"published":{"date-parts":[[2017,12]]},"assertion":[{"value":"2017-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-10-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01461-17"}}