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Targeting Mycobacterium tuberculosis response to environmental cues for the development of effective antitubercular drugs.
PLOS Biology ( IF 7.8 ) Pub Date : 2021-07-28 , DOI: 10.1371/journal.pbio.3001355
Richard C Lavin 1, 2 , Calvin Johnson 1 , Yong-Mo Ahn 3 , Kyle M Kremiller 3 , Matthew Sherwood 3 , Jimmy S Patel 3 , Yan Pan 4 , Riccardo Russo 5 , Nathan J MacGilvary 1 , David Giacalone 1, 2 , Yuzo L Kevorkian 1, 2 , Matthew D Zimmerman 4 , J Fraser Glickman 6 , Joel S Freundlich 3, 5 , Shumin Tan 1, 2
Affiliation  

Sensing and response to environmental cues, such as pH and chloride (Cl-), is critical in enabling Mycobacterium tuberculosis (Mtb) colonization of its host. Utilizing a fluorescent reporter Mtb strain in a chemical screen, we have identified compounds that dysregulate Mtb response to high Cl- levels, with a subset of the hits also inhibiting Mtb growth in host macrophages. Structure-activity relationship studies on the hit compound "C6," or 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole, demonstrated a correlation between compound perturbation of Mtb Cl- response and inhibition of bacterial growth in macrophages. C6 accumulated in both bacterial and host cells, and inhibited Mtb growth in cholesterol media, but not in rich media. Subsequent examination of the Cl- response of Mtb revealed an intriguing link with bacterial growth in cholesterol, with increased transcription of several Cl--responsive genes in the simultaneous presence of cholesterol and high external Cl- concentration, versus transcript levels observed during exposure to high external Cl- concentration alone. Strikingly, oral administration of C6 was able to inhibit Mtb growth in vivo in a C3HeB/FeJ murine infection model. Our work illustrates how Mtb response to environmental cues can intersect with its metabolism and be exploited in antitubercular drug discovery.

中文翻译:

靶向结核分枝杆菌对环境线索的反应,以开发有效的抗结核药物。

对环境线索(如 pH 值和氯化物 (Cl-))的感知和响应对于使结核分枝杆菌 (Mtb) 能够在其宿主中定殖至关重要。在化学筛选中利用荧光报告基因 Mtb 菌株,我们已经确定了使 Mtb 对高 Cl-水平反应失调的化合物,其中一部分命中也抑制了宿主巨噬细胞中的 Mtb 生长。对命中化合物“C6”或 2-(4-((2-(ethylthio)pyrimidin-5-yl)methyl)piperazin-1-yl)benzo[d]oxazole 的构效关系研究表明Mtb Cl-反应的复合扰动和巨噬细胞中细菌生长的抑制。C6 在细菌和宿主细胞中积累,在胆固醇培养基中抑制 Mtb 生长,但在富培养基中没有。随后对 Mtb 的 Cl-反应的检查揭示了与胆固醇中细菌生长的有趣联系,在胆固醇和高外部 Cl- 浓度同时存在的情况下,几个 Cl-反应基因的转录增加,而在暴露于高浓度时观察到的转录水平单独的外部 Cl- 浓度。引人注目的是,在 C3HeB/FeJ 鼠感染模型中,口服 C6 能够抑制体内 Mtb 生长。我们的工作说明了 Mtb 对环境线索的反应如何与其代谢相交,并在抗结核药物发现中被利用。与单独暴露于高外部 Cl- 浓度期间观察到的转录水平。引人注目的是,在 C3HeB/FeJ 鼠感染模型中,口服 C6 能够抑制体内 Mtb 生长。我们的工作说明了 Mtb 对环境线索的反应如何与其代谢相交,并在抗结核药物发现中被利用。与单独暴露于高外部 Cl- 浓度期间观察到的转录水平。引人注目的是,在 C3HeB/FeJ 鼠感染模型中,口服 C6 能够抑制体内 Mtb 生长。我们的工作说明了 Mtb 对环境线索的反应如何与其代谢相交,并在抗结核药物发现中被利用。
更新日期:2021-07-28
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