{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T20:02:55Z","timestamp":1776024175729,"version":"3.50.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Key R&D Program of China","award":["2017YFD0500302"],"award-info":[{"award-number":["2017YFD0500302"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31730005"],"award-info":[{"award-number":["31730005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of Hubei Province","award":["2018CFB495"],"award-info":[{"award-number":["2018CFB495"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2662016QD007"],"award-info":[{"award-number":["2662016QD007"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute and Chinese Academy of Agricultural Sciences","award":["SKLVEB2016KFKT008"],"award-info":[{"award-number":["SKLVEB2016KFKT008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>It is urgent to understand the regulatory mechanism of drug resistance in widespread bacterial pathogens. In Mycobacterium tuberculosis, several transcriptional regulators have been found to play essential roles in regulating its drug resistance. In this study, we found that an ArsR family transcription regulator encoded by Rv2642 (CdiR) responds to isoniazid (INH), a widely used anti-tuberculosis (TB) drug. CdiR negatively regulates self and adjacent genes, including arsC (arsenic-transport integral membrane protein ArsC). CdiR directly interacts with INH and Cd(II). The binding of INH and Cd(II) both reduce its DNA-binding activity. Disrupting cdiR increased the drug susceptibility to INH, whereas overexpressing cdiR decreased the susceptibility. Strikingly, overexpressing arsC increased the drug susceptibility as well as cdiR. Additionally, both changes in cdiR and arsC expression caused sensitivity to other drugs such as rifamycin and ethambutol, where the minimal inhibitory concentrations in the cdiR deletion strain were equal to those of the arsC-overexpressing strain, suggesting that the function of CdiR in regulating drug resistance primarily depends on arsC. Furthermore, we found that Cd(II) enhances bacterial resistance to INH in a CdiR-dependent manner. As a conclusion, CdiR has a critical role in directing the interplay between Cd(II) metal ions and drug susceptibility in mycobacteria.<\/jats:p>","DOI":"10.1093\/jb\/mvaa086","type":"journal-article","created":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T11:09:21Z","timestamp":1595070561000},"page":"43-53","source":"Crossref","is-referenced-by-count":3,"title":["Cd(II)-binding transcriptional regulator interacts with isoniazid and regulates drug susceptibility in mycobacteria"],"prefix":"10.1093","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2924-5717","authenticated-orcid":false,"given":"Min","family":"Yang","sequence":"first","affiliation":[{"name":"College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi-Hua","family":"Jia","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Ling","family":"Tao","sequence":"additional","affiliation":[{"name":"International Agricultural Institute, Yunnan Academy of Agricultural Sciences, Kunming 650224, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wan-Zhong","family":"Jia","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730046, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Hua","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-7939","authenticated-orcid":false,"given":"Chun-Hui","family":"Gao","sequence":"additional","affiliation":[{"name":"College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,7,24]]},"reference":[{"key":"2021020714255626900_mvaa086-B1","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/ng.3767","article-title":"Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance","volume":"49","author":"Manson","year":"2017","journal-title":"Nat. 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Chem"},{"key":"2021020714255626900_mvaa086-B27","doi-asserted-by":"crossref","first-page":"2726","DOI":"10.1111\/febs.12815","article-title":"Characterization of the interaction between a SirR family transcriptional factor of Mycobacterium tuberculosis, encoded by Rv2788, and a pair of toxin-antitoxin proteins RelJ\/K, encoded by Rv3357 and Rv3358","volume":"281","author":"Yang","year":"2014","journal-title":"FEBS J"},{"key":"2021020714255626900_mvaa086-B28","doi-asserted-by":"crossref","first-page":"16741","DOI":"10.1074\/jbc.RA118.002693","article-title":"Molecular mechanism of the synergistic activity of ethambutol and isoniazid against Mycobacterium tuberculosis","volume":"293","author":"Zhu","year":"2018","journal-title":"J. Biol. 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