适体
支原体
结核分枝杆菌
指数富集配体系统进化
DNA
生物
生物信息学
响应调节器
转录因子
血浆蛋白结合
结合位点
细胞生物学
计算生物学
生物物理学
化学
生物化学
遗传学
基因
突变体
核糖核酸
肺结核
医学
病理
作者
Priyanka Chauhan,Ishara Datta,Abhijeet Dhiman,Uma Shankar,Amit Kumar,Atul Vashist,Tarun Sharma,Jaya Sivaswami Tyagi
出处
期刊:ACS Infectious Diseases
[American Chemical Society]
日期:2022-11-04
卷期号:8 (12): 2540-2551
被引量:2
标识
DOI:10.1021/acsinfecdis.2c00414
摘要
Tuberculosis is recognized as one of the major public health threats worldwide. The DevR-DevS (DosR/DosS) two-component system is considered a novel drug target in Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, owing to its central role in bacterial adaptation and long-term persistence. An increase in DevR levels and the decreased permeability of the mycobacterial cell wall during hypoxia-associated dormancy pose formidable challenges to the development of anti-DevR compounds. Using an in vitro evolution approach of Systematic Evolution of Ligands by EXponential enrichment (SELEX), we developed a panel of single-stranded DNA aptamers that interacted with Mtb DevR protein in solid-phase binding assays. The best-performing aptamer, APT-6, forms a G-quadruplex structure and inhibits DevR-dependent transcription in Mycobacterium smegmatis. Mechanistic studies indicate that APT-6 functions by inhibiting the dimerization and DNA binding activity of DevR protein. In silico studies reveal that APT-6 interacts majorly with C-terminal domain residues that participate in DNA binding and formation of active dimer species of DevR. To the best of our knowledge, this is the first report of a DNA aptamer that inhibits the function of a cytosolic bacterial response regulator. By inhibiting the dimerization of DevR, APT-6 targets an essential step in the DevR activation mechanism, and therefore, it has the potential to universally block the expression of DevR-regulated genes for intercepting dormancy pathways in mycobacteria. These findings also pave the way for exploring aptamer-based approaches to design and develop potent inhibitors against intracellular proteins of various bacterial pathogens of global concern.
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