新型抗结核药物BBD的筛选及作用机制初探

发布时间：2018-04-28 19:45

本文选题：抗结核药物 + BBD　；参考：《中国病原生物学杂志》2017年07期

【摘要】：目的筛选新型抗结核药物BBD并探讨其作用机制。方法建立基于分枝杆菌感染宿主细胞模型的高通量抗结核药物筛选体系进行药物筛选,通过高效液相HLPC以及SD大鼠的药物代谢动力学实验等研究筛选药物BBD的作用机制。结果筛选出一种新型抗结核药物BBD,该药能抑制细胞内、细胞外分枝杆菌的生长,甚至能抑制耐多药临床分离株结核菌的生长。BBD能够穿越A549细胞和THP-1细胞的细胞膜从而抑制胞内寄生菌的生长。Labelfree定量蛋白质组学分析BBD处理后牛型结核分支杆菌BCG的蛋白质组表达谱发生显著变化,变化主要集中在膜相关系统和核糖体,尤其对核糖体的功能和氧化磷酸化等代谢通路有明显的抑制作用。SD大鼠药物代谢动力学实验表明,用药期间血浆药物浓度最高为BBD体外MIC的3.5倍,半衰期约为4h。结论 BBD具有良好的穿膜效果,能快速被机体吸收。该药还能抑制胞内结核菌的生长,有望成为新型抗结核药物。
[Abstract]:Objective to screen new anti-tuberculosis drug BBD and to explore its mechanism. Methods A high-throughput anti-tuberculosis drug screening system was established based on the host cell model of Mycobacterium infection. The mechanism of drug BBD was screened by high performance liquid phase (HLPC) and pharmacokinetic experiments in SD rats. Results A novel anti-tuberculosis drug BBD was screened, which can inhibit the growth of intracellular and extracellular mycobacteria. It can even inhibit the growth of Mycobacterium tuberculosis. BBD can traverse the cell membrane of A549 cells and THP-1 cells and thus inhibit the growth of intracellular parasites. Quantitative proteomics Analysis of Mycobacterium Bovis BCG treated with BBD There were significant changes in the proteome expression profile, The changes were mainly concentrated in the membrane-related system and ribosomes, especially in the inhibition of ribosomal function and oxidative phosphorylation. The plasma concentration was 3.5 times as high as that of MIC in vitro of BBD, and the half-life was about 4 h. Conclusion BBD has good membrane penetration effect and can be quickly absorbed by the body. The drug can also inhibit the growth of intracellular tuberculous bacteria, and is expected to become a new anti-tuberculosis drug.
【作者单位】：上海大学生命科学院;中国科学院上海巴斯德研究所;复旦大学上海医学院基础医学院病原生物学系;
【基金】：国家自然科学基金项目(No.KRF101397) 上海市自然科学基金项目(No.14ZR1444300)
【分类号】：R978.3

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