{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:44:01Z","timestamp":1788313441415,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013190","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000}}],"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013290","name":"National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"publisher","award":["2023YFC2307305"],"award-info":[{"award-number":["2023YFC2307305"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Major Project of Guangzhou National Laboratory","award":["GZNL2024A01024"],"award-info":[{"award-number":["GZNL2024A01024"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170176"],"award-info":[{"award-number":["32170176"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Sailing Program","award":["22YF1445700"],"award-info":[{"award-number":["22YF1445700"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Mycobacterium abscessus<\/jats:italic> (<jats:italic>MAB<\/jats:italic>) is a clinically significant multidrug-resistant (MDR) pathogen, particularly implicated in pulmonary infections among cystic fibrosis (CF) patients. Tedizolid (TZD), an oxazolidinone-class antibacterial drug, has been recommended as an alternative treatment for <jats:italic>MAB<\/jats:italic>-infected patients who are intolerant to or whose isolate is resistant to first-line drugs including linezolid (LZD). To investigate the TZD resistance mechanisms in <jats:italic>MAB<\/jats:italic>, we isolated 23 TZD-resistant <jats:italic>MAB<\/jats:italic> mutants and performed whole-genome sequencing (WGS) to identify resistance-associated genes. Frequent mutations were identified in <jats:italic>MAB_2885<\/jats:italic>, encoding a putative TetR transcriptional regulator, and <jats:italic>MAB_2303<\/jats:italic>, encoding a putative mycobacterial membrane protein large (MmpL). Drug susceptibility testing confirmed that <jats:italic>MAB_2885<\/jats:italic> mutations contribute to both TZD and LZD resistance in <jats:italic>MAB<\/jats:italic>. RNA-seq analysis revealed that restoring wild-type <jats:italic>MAB_2885<\/jats:italic> in mutants downregulated the <jats:italic>MAB_2302-MAB_2303<\/jats:italic>. Electrophoretic mobility shift assay (EMSA) showed the MAB_2885 protein binds to its target sequence upstream of <jats:italic>MAB_2302-MAB_2303<\/jats:italic>, further confirming their regulatory relationship. The W91R mutation in the MAB_2885 protein was found to impair its DNA-binding activity compared to the wild-type. Liquid chromatography-tandem mass spectrometry (LC-MS\/MS) analysis confirmed that MAB_2302-MAB_2303 functions as a TZD efflux pump. Additionally, overexpression of <jats:italic>MAB_2885<\/jats:italic> in <jats:italic>M. abscessus<\/jats:italic> subsp. <jats:italic>bolletii and M. abscessus<\/jats:italic> subsp. <jats:italic>massiliense<\/jats:italic> also increased their TZD susceptibility and downregulated their respective MmpS-MmpL orthologs. Overall, our study demonstrates that mutations in <jats:italic>MAB_ 2885<\/jats:italic> contribute to TZD and LZD resistance by disrupting the negative regulation of the downstream MAB_2302-MAB_2303, which functions as a direct efflux pump for TZD. These findings provide new insights into oxazolidinone resistance mechanisms in <jats:italic>MAB<\/jats:italic> and identify potential biomarkers for detecting drug resistance.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013190","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T17:46:18Z","timestamp":1748627178000},"page":"e1013190","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mutations in the transcriptional regulator MAB_2885 confer tedizolid and linezolid resistance through the MmpS-MmpL efflux pump MAB_2302-MAB_2303 in Mycobacterium abscessus"],"prefix":"10.1371","volume":"21","author":[{"given":"Huiyun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenya","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siran","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-3766","authenticated-orcid":true,"given":"Jiazhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"issue":"1","key":"ppat.1013190.ref001","article-title":"Rapidly 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