{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:27:28Z","timestamp":1792787248129,"version":"4.5.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"publisher","award":["2021YFA1300904"],"award-info":[{"award-number":["2021YFA1300904"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"China-Maurice Wilkins Centre (MWC) Programme-Guangdong-New Zealand Bilateral Joint Funding","award":["2025A0505020001"],"award-info":[{"award-number":["2025A0505020001"]}],"id":[{"id":"https:\/\/ror.org\/0327mmx61","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82302554"],"award-info":[{"award-number":["82302554"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82502762"],"award-info":[{"award-number":["82502762"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Technologies Research and Development Program of Guangzhou Municipality","award":["2025B01J3019"],"award-info":[{"award-number":["2025B01J3019"]}]},{"name":"Guangzhou National Laboratory and State Key Laboratory of Respiratory Disease","award":["GZNL2025B01006"],"award-info":[{"award-number":["GZNL2025B01006"]}],"id":[{"id":"https:\/\/ror.org\/04hja5e04","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Major Project of Guangzhou National Laboratory","award":["GZNL2025C01003"],"award-info":[{"award-number":["GZNL2025C01003"]}],"id":[{"id":"https:\/\/ror.org\/03ybmxt82","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n \n \n Mycobacterium abscessus<\/jats:italic>\n is a rapidly growing non-tuberculous mycobacterium with rising global incidence. This pathogen exhibits intrinsic resistance to most antibiotics, presenting a major public health threat. Ethionamide (ETH) requires bioactivation by monooxygenase EthA to form the active ETH-NAD adduct. We previously identified MAB_3513 (NudC) as a phosphohydrolase that confers intrinsic resistance to\n M. abscessus<\/jats:italic>\n by hydrolyzing this adduct. However, deletion of\n nudC<\/jats:italic>\n results in only partial susceptibility to ETH, indicating the existence of additional resistance mechanisms. This study identified MAB_0984 as the EthR regulator in\n M. abscessus<\/jats:italic>\n . Deletion of\n ethR<\/jats:italic>\n in a\n nudC<\/jats:italic>\n knockout background (\u0394\u0394\n ethR<\/jats:italic>\n ) significantly enhanced ETH-NAD adduct accumulation, leading to hypersusceptibility to ETH. Notably, the \u0394\n ethR<\/jats:italic>\n mutant exhibited higher susceptibility than \u0394\n nudC<\/jats:italic>\n , demonstrating that EthR is a more dominant mediator of ETH resistance than NudC. Furthermore, MAB_0985 (EthA1) and MAB_0103 (EthA2) are the principal ETH-activating monooxygenases in\n M. abscessus<\/jats:italic>\n . Deletion of either gene alone or in combination in the \u0394\n nudC<\/jats:italic>\n reduced adduct formation and increased resistance, while the triple mutant \u0394\u0394\n ethA1<\/jats:italic>\n \u0394\n ethA2<\/jats:italic>\n restored wild-type resistance. Using an intergenic region-enhanced green fluorescent protein reporter system and quantitative reverse transcription-PCR, we demonstrated that EthR confers resistance by specifically suppressing\n ethA1<\/jats:italic>\n expression in\n M. abscessus<\/jats:italic>\n . The\n Mycobacterium tuberculosis<\/jats:italic>\n EthR inhibitor BDM31343 could boost the efficacy of ETH against\n M. abscessus<\/jats:italic>\n by inhibiting EthR. Collectively, this study identified the\n ethR<\/jats:italic>\n and\n ethA<\/jats:italic>\n genes in\n M. abscessus<\/jats:italic>\n for the first time and elucidated their role in mediating resistance to ETH. Therefore, EthR is a promising target for potentiating the efficacy of ETH against\n M. abscessus<\/jats:italic>\n .\n <\/jats:p>\n \n IMPORTANCE<\/jats:title>\n \n Mycobacterium abscessus<\/jats:italic>\n constitutes an escalating global health threat, primarily due to its intrinsic resistance to most antibiotics. This study identifies MAB_0984 (EthR) as a dominant resistance determinant that exerts a more profound impact on ethionamide (ETH) susceptibility than the previously characterized NudC. We demonstrate that EthR mediates resistance by specifically repressing the expression of EthA1 (MAB_0985), one of the primary monooxygenases responsible for ETH bioactivation. The\n Mycobacterium tuberculosis<\/jats:italic>\n EthR inhibitor BDM31343 potentiated the activity of ETH against\n M. abscessus<\/jats:italic>\n through inhibition of EthR. These findings elucidate the mechanism of ETH resistance in\n M. abscessus<\/jats:italic>\n , identifying EthR as a promising target for boosting the efficacy of ETH against\n M. abscessus<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n <\/jats:sec>","DOI":"10.1128\/spectrum.00638-26","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:01:07Z","timestamp":1787922067000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Identification and characterization of\n ethR<\/i>\n and\n ethA<\/i>\n genes impacting the sensitivity of\n Mycobacterium abscessus<\/i>\n to ethionamide"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9410-4438","authenticated-orcid":false,"given":"Xiaofan","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/01px77p81","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/04c4dkn09","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, University of Science and Technology of China","place":["Hefei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwen","family":"Lu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohui","family":"Duan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01px77p81","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-9547","authenticated-orcid":true,"given":"H. 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