{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T22:34:28Z","timestamp":1762641268301,"version":"build-2065373602"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"National Infectious Disease Medical Center","award":["B2022011-1"],"award-info":[{"award-number":["B2022011-1"]}]},{"name":"Jinan Microecological Biomedicine Shandong Laboratory","award":["JNL-2022050B"],"award-info":[{"award-number":["JNL-2022050B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Clofazimine is a promising repurposed drug for treating Mycobacterium avium-intracellulare complex pulmonary disease, but its resistance mechanisms in Mycobacterium intracellulare remain poorly understood.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n This study aims to elucidate the resistance mechanisms of M. intracellulare to clofazimine.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We isolated 36 clofazimine-resistant M. intracellulare mutants in vitro and performed whole-genome sequencing to identify resistance-associated mutations. Gene complementation was used to validate the role of the identified mutations.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n We identified various mutations in the marR gene (WP_009952290.1) in 61% of clofazimine-resistant mutants by whole-genome sequencing. Mutations were identified in additional genes encoding ssuD (flavin-dependent oxidoreductase, C67A), lppI (membrane lipoprotein, C207 deletion), GMC oxidoreductase (glucose-methanol-choline oxidoreductase, G157 deletion), MASE1 domain-containing protein (C62G) and PPE family protein (222C deletion). Gene complementation experiments demonstrated that introducing the wild-type marR in clofazimine-resistant strain (L72) with marR mutations reduced clofazimine MIC from 1 mg\/L to susceptible baseline (0.25 mg\/L), confirming its critical role in clofazimine resistance. Notably, the M. intracellulare MarR lacks homology to Mycobacterium tuberculosis MarR family protein Rv0678 (MmpR) involved in clofazimine and bedaquiline resistance but is flanked by non-efflux pump genes (dhmA and doxX), and unlike M. tuberculosis, its mutation does not cause bedaquiline cross-resistance, indicating a different MarR and distinct regulatory mechanism for clofazimine resistance in M. intracellulare.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n This work highlights marR as a key determinant of clofazimine resistance in M. intracellulare and underscores the need for further mechanistic studies with implications for rapid molecular detection and effective treatment.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/jac\/dkaf321","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T11:19:52Z","timestamp":1755515992000},"page":"2954-2957","source":"Crossref","is-referenced-by-count":0,"title":["Novel mutations associated with clofazimine resistance in\n Mycobacterium intracellulare<\/i>"],"prefix":"10.1093","volume":"80","author":[{"given":"Xiuzhi","family":"Jiang","sequence":"first","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]},{"name":"Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 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and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]},{"name":"Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]},{"name":"Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pusheng","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University 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Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]},{"name":"Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 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Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug Development, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]},{"name":"Yuhang Institute for Collaborative Innovation and Translational Research in Life Sciences and Technology, Zhejiang University School of Medicine , Hangzhou, Zhejiang 310003 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, China-Singapore Belt and Road Joint Laboratory on Infection Research and Drug 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