With the emerging primary resistance of Mycobacterium tuberculosis to current drugs and wide distribution of latent tuberculosis infection, the need for new compounds with a novel mode of action is growing. Copper-mediated innate immunity and its antibacterial toxicity pose novel strategies for tuberculosis drug discovery and development. Transcriptome response to 1-hydroxy-5-R-pyridine-2(1H)-thiones, which were found to be highly active in vitro against actively growing and dormant nonculturable M. tuberculosis, revealed signs of copper toxicity. 1-Hydroxy-5-R-pyridine-2(1H)-thiones were found to form stable charged lipophilic complexes with Cu²⁺ ions that could transport into mycobacterial cells. Copper accumulated inside treated bacilli as subsequent metabolic destruction of the complex led to chemical transformation of 1-hydroxy-5-R-pyridine-2(1H)-thiones and release of free Cu²⁺ into the cytoplasm. 1-Hydroxy-5-R-pyridine-2(1H)-thiones are a potent class of Cu-dependent inhibitors of M. tuberculosis, and may control infection by impairment of copper homeostasis.

中文翻译：

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1-羟基-5 - R-吡啶-2（1H）-硫 酮在复制和休眠的结核分枝杆菌中与铜有关的毒性†

随着结核分枝杆菌对当前药物的新出现的主要耐药性以及潜伏性结核感染的广泛分布，对具有新颖作用方式的新化合物的需求正在增长。铜介导的先天免疫及其抗菌毒性为结核病药物的发现和开发提出了新的策略。转录组对1-羟基-5 - R-吡啶-2（1 H）-硫酮的反应，被发现在体外对活跃生长和休眠的不可培养的结核分枝杆菌具有很高的活性，显示出铜毒性的迹象。发现1-羟基-5 - R-吡啶-2（1 H）-硫酮与铜形成稳定的带电亲脂性络合物²⁺离子可以转运到分枝杆菌细胞中。铜在处理过的细菌中积累，随后对该复合物进行代谢破坏，从而导致1-羟基-5- R-吡啶-2（1 H）-硫酮的化学转化，并释放出游离的Cu ²⁺进入细胞质。1-Hydroxy-5- R -pyridine-2（1 H）-thiones是一类强效的结核分枝杆菌铜依赖性抑制剂，可通过铜稳态失衡来控制感染。