Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.
Iron limitation in M. tuberculosis has broad impact on central carbon metabolism.
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DOI：
10.1038/s42003-022-03650-z
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发表时间：
2022-07-09
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
结核分枝杆菌(Mtb)是人类肺病结核病(TB)的病因，每年造成约150万人死亡。先前的工作已经证实，脂类在体内被结核分枝杆菌主动分解，并在结核分枝杆菌的生理和发病机制中发挥重要作用。我们进行了高通量筛选，以确定其宿主巨噬细胞中结核分枝杆菌存活的抑制物。本屏幕中确定的热门化合物之一，sAEL057，在胆固醇为主要碳源的条件下显示出对结核分枝杆菌生长的最高活性。转录和功能数据表明，sAEL057作为铁络合剂限制了Mtb对铁的获取。此外，药物和遗传抑制铁的获取会导致胆固醇分解代谢的失调，揭示了这些途径之间以前不为人知的联系。对SAEL057的S作用模式的描述认为，结核分枝杆菌的代谢调节揭示了那些影响中央碳代谢的途径中的脆弱性。一种结核分枝杆菌(Mtb)存活的抑制物起到了铁螯合剂的作用，表明缺铁会改变Mtb胆固醇和中心碳代谢。
Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrates highest activity on Mtb growth in conditions where cholesterol was the primary carbon source. Transcriptional and functional data indicate that sAEL057 limits Mtb’s access to iron by acting as an iron chelator. Furthermore, pharmacological and genetic inhibition of iron acquisition results in dysregulation of cholesterol catabolism, revealing a previously unappreciated linkage between these pathways. Characterization of sAEL057’s mode of action argues that Mtb’s metabolic regulation reveals vulnerabilities in those pathways that impact central carbon metabolism. An inhibitor of Mycobacterium tuberculosis (Mtb) survival acts as an iron chelator, demonstrating that iron deprivation alters Mtb cholesterol and central carbon metabolism.
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作者：
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发表时间：
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期刊：
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影响因子：
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通讯作者：
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DOI：
10.1084/jem.20172020
发表时间：
2018-04-02
期刊：
The Journal of experimental medicine
影响因子：
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