Abstract

Mycobacterium tuberculosis (Mtb) has an old history as a human pathogen and still kills over one million people every year. One key feature of this bacterium is its dormancy: a phenomenon responsible for major changes in its metabolism and replication that have been associated with the need for a lengthy therapy for Mtb. This process is regulated by key heme-based sensors, particularly DosT and DevS (DosS), among other co-regulators, and also linked to nitrogen utilization (nitrate/nitrite) and stringent responses. In face of the current threat of tuberculosis, there is an urgent need to develop new therapeutic agents capable of targeting the dormant state, associated with the need for a lengthy therapy. Interestingly, many of those key proteins are indeed metallo-containing or metallo-dependent biomolecules, opening exciting bioinorganic opportunities. Here, we critically reviewed a series of small molecules targeting key proteins involved in these processes, including DosT/DevS/DevR, RegX3, MprA, MtrA, NarL, PknB, Rel, PPK, nitrate and nitrite reductases, GlnA1, aiming for new opportunities and alternative therapies.

Graphic abstract

In the battle against Mycobacterium tuberculosis, new drug targets must be searched, in particular those involved in dormancy. A series of exciting cases for drug development involving metallo-containing or metallo-dependent biomolecules are reviewed, opening great opportunities for the bioinorganic chemistry community.

中文翻译：

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睡眠病原体的潜在治疗方法：结核病是一种生物无机化学的案例。

摘要

结核分枝杆菌（Mtb）作为人类病原体历史悠久，每年仍然有100万人丧生。这种细菌的一个主要特征是它的休眠状态：一种导致其代谢和复制发生重大变化的现象，这种现象与需要长期治疗Mtb有关。此过程由主要的基于血红素的传感器（尤其是DosT和DevS（DosS））以及其他协同调节器进行调节，并且还与氮利用（硝酸盐/亚硝酸盐）和严格的响应有关。面对当前的结核病威胁，迫切需要开发能够靶向休眠状态的新治疗剂，并且需要长期的治疗。有趣的是，这些关键蛋白质中的许多确实是含金属或金属依赖性生物分子，这为生物无机带来了令人兴奋的机会。这里，

图形摘要

在对抗结核分枝杆菌的斗争中，必须寻找新的药物靶标，尤其是那些与休眠有关的靶标。审查了一系列激动人心的涉及含金属或金属依赖性生物分子的药物开发案例，为生物无机化学界提供了巨大的机会。