Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence
Inhibiting the stringent response blocks Mycobacterium tuberculosis entry into quiescence and reduces persistence
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DOI：
10.1126/sciadv.aav2104
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发表时间：
2019-03-01
期刊：
影响因子：
13.6
通讯作者：
Karakousis, Petros C.
中科院分区：
文献类型：
--
作者：
Dutta, Noton K.;Klinkenberg, Lee G.;Karakousis, Petros C.
严格的反应使结核分枝杆菌（Mtb）在各种压力下关闭其复制和代谢。本研究表明，缺乏严格反应酶Rel（Mtb）的Mtb在营养饥饿期间无法减慢其复制速率。代谢组学分析显示，营养匮乏的雷尔（Mtb）缺乏菌株的代谢增加与在营养丰富的肉汤中呈指数增长的野生型细菌相似，与无法进入静止状态一致。在营养饥饿和慢性感染小鼠的肺部，缺乏雷尔（Mtb）增加了突变细菌对异烟肼杀死的易感性。我们筛选了一个含有200多万种Rel（Mtb）抑制剂的药物文库，结果表明先导化合物X9能够直接杀死营养匮乏的结核分枝杆菌，并增强了异烟肼的杀伤活性。抑制Rel（Mtb）是一种很有希望的针对结核分枝杆菌的方法，有可能缩短结核病治疗的持续时间。
The stringent response enables Mycobacterium tuberculosis (Mtb) to shut down its replication and metabolism under various stresses. Here we show that Mtb lacking the stringent response enzyme Rel(Mtb) was unable to slow its replication rate during nutrient starvation. Metabolomics analysis revealed that the nutrient-starved rel(Mtb)-deficient strain had increased metabolism similar to that of exponentially growing wild-type bacteria in nutrient-rich broth, consistent with an inability to enter quiescence. Deficiency of rel(Mtb) increased the susceptibility of mutant bacteria to killing by isoniazid during nutrient starvation and in the lungs of chronically infected mice. We screened a pharmaceutical library of over 2 million compounds for inhibitors of Rel(Mtb) and showed that the lead compound X9 was able to directly kill nutrient-starved M. tuberculosis and enhanced the killing activity of isoniazid. Inhibition of Rel(Mtb) is a promising approach to target M. tuberculosis persisters, with the potential to shorten the duration of TB treatment.