Potent Inhibitors of Mycobacterium tuberculosis Growth Identified by Using in-Cell NMR-based Screening,ACS Chemical Biology

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Potent Inhibitors of Mycobacterium tuberculosis Growth Identified by Using in-Cell NMR-based Screening
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-01-23 00:00:00 , DOI: 10.1021/acschembio.7b00879
Christopher M. DeMott ₁ , Roxie Girardin ₂ , Jacqueline Cobbert ₁ , Sergey Reverdatto ₁ , David S. Burz ₁ , Kathleen McDonough _{2,

3} , Alexander Shekhtman ₁

Affiliation

In-cell NMR spectroscopy was used to screen for drugs that disrupt the interaction between prokaryotic ubiquitin like protein, Pup, and mycobacterial proteasome ATPase, Mpa. This interaction is critical for Mycobacterium tuberculosis resistance against nitric oxide (NO) stress; interruption of this process was proposed as a mechanism to control latent infection. Three compounds isolated from the NCI Diversity set III library rescued the physiological proteasome substrate from degradation suggesting that the proteasome degradation pathway was selectively targeted. Two of the compounds bind to Mpa with sub-micromolar to nanomolar affinity, and all three exhibit potency toward mycobacteria comparable to antibiotics currently available on the market, inhibiting growth in the low micromolar range.

中文翻译：

通过使用基于细胞核磁共振的筛选确定结核分枝杆菌生长的有效抑制剂。

细胞内NMR光谱用于筛选破坏原核泛素如蛋白Pup和分枝杆菌蛋白酶ATPase Mpa之间相互作用的药物。这种相互作用对于结核分枝杆菌对一氧化氮（NO）胁迫的抗性至关重要。提议中断该过程作为控制潜伏感染的机制。从NCI多样性III组文库中分离出的三种化合物可挽救生理性蛋白酶体底物免于降解，这表明蛋白酶体的降解途径是有针对性的。其中两种化合物以亚微摩尔至纳摩尔的亲和力与Mpa结合，并且所有三种化合物均表现出对分枝杆菌的效力，与目前市场上可买到的抗生素相当，从而抑制了在低微摩尔范围内的生长。

更新日期：2018-01-23

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