Structural and functional studies of the Mycobacterium tuberculosis VapBC30 toxin-antitoxin system: implications for the design of novel antimicrobial peptides.
Structural and functional studies of the Mycobacterium tuberculosis VapBC30 toxin-antitoxin system: implications for the design of novel antimicrobial peptides.
复制标题
DOI：
10.1093/nar/gkv689
复制
发表时间：
2015-09-03
影响因子：
14.9
通讯作者：
Lee BJ
中科院分区：
文献类型：
--
作者：
Lee IG;Lee SJ;Chae S;Lee KY;Kim JH;Lee BJ
毒素-抗毒素（TA）系统在细菌生理学中发挥着重要作用，例如多药耐受、生物膜形成和应激条件下细胞生长的停滞。为了开发针对结核病的新型抗菌药物，我们重点研究了 VapBC 系统，该系统包含结核分枝杆菌中一半以上的 TA 系统。在这里，我们报告结核分枝杆菌 VapC30 毒素通过镁和锰离子依赖性核糖核酸酶活性调节细胞生长，并被同源 VapB30 抗毒素抑制。我们还确定了结核分枝杆菌 VapBC30 复合物的 2.7 Å 分辨率晶体结构，揭示了通过 VapB30 抗毒素的交换阻断来灭活 VapC30 毒素的新过程。我们对结核分枝杆菌VapBC30的研究引导我们设计了两种基于VapB30和VapC30的新型肽，它们成功地破坏了毒素-抗毒素复合物，从而激活了VapC30毒素的核糖核酸酶活性。我们的发现可能为下一代治疗结核病铺平道路。
Toxin-antitoxin (TA) systems play important roles in bacterial physiology, such as multidrug tolerance, biofilm formation, and arrest of cellular growth under stress conditions. To develop novel antimicrobial agents against tuberculosis, we focused on VapBC systems, which encompass more than half of TA systems in Mycobacterium tuberculosis. Here, we report that theMycobacterium tuberculosis VapC30 toxin regulates cellular growth through both magnesium and manganese ion-dependent ribonuclease activity and is inhibited by the cognate VapB30 antitoxin. We also determined the 2.7-Å resolution crystal structure of the M. tuberculosis VapBC30 complex, which revealed a novel process of inactivation of the VapC30 toxin via swapped blocking by the VapB30 antitoxin. Our study on M. tuberculosis VapBC30 leads us to design two kinds of VapB30 and VapC30-based novel peptides which successfully disrupt the toxin-antitoxin complex and thus activate the ribonuclease activity of the VapC30 toxin. Our discovery herein possibly paves the way to treat tuberculosis for next generation.