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 isoniazid, 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.

中文翻译：

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结合镉（II）的转录调节剂与异烟肼相互作用，并调节分枝杆菌的药物敏感性。

迫切需要了解广泛细菌病原体中耐药性的调控机制。在结核分枝杆菌中，已发现几种转录调节剂在调节其耐药性中起着重要作用。在这项研究中，我们发现由Rv2642（CdiR）编码的ArsR家族转录调节剂对异烟肼（INH）（一种广泛使用的抗结核（TB）药物）有反应。CdiR负调控自身和邻近基因，包括arsC（砷转运整合膜蛋白ArsC）。CdiR与INH和Cd（II）直接相互作用。INH和Cd（II）的结合都降低了其DNA结合活性。破坏cdiR会增加药物对异烟肼的敏感性，而过度表达cdiR降低了药敏性。令人惊讶的是，过表达arsC会增加药物敏感性以及cdiR。此外，cdiR和arsC表达的变化都引起了对其他药物（如利福霉素和乙胺丁醇）的敏感性，其中cdiR缺失菌株中的最小抑菌浓度等于过表达arsC的菌株的最小抑菌浓度，表明CdiR在调节药物中的功能抵抗力主要取决于arsC。此外，我们发现Cd（II）以CdiR依赖的方式增强了细菌对INH的抵抗力。结论是，CdiR在指导Cd（II）金属离子与分枝杆菌药物敏感性之间的相互作用中起着至关重要的作用。