Toxin–antitoxin (TA) systems have been considered essential factors for bacterial survival. During our drug development program aimed against tuberculosis (TB), we discovered certain peptides that mimic the binding of the VapBC30 complex, leading to the arrest of bacterial cell growth and eventually cell death. Herein, we optimized these candidate peptides based on a hydrocarbon stapling strategy and performed biological in vitro evaluations. The V30-SP-8 peptide successfully penetrated Mycobacterium smegmatis cell membranes and exerted bactericidal activity at a minimum inhibitory concentration that inhibited 50% of the isolates (MIC₅₀) < 6.25 μM. With the aid of structural and biochemical information for the VapBC30 TA system from M. tuberculosis, we suggest potential antimicrobial agents that could provide a platform to establish a novel antibacterial strategy. Reflecting the limited number of therapeutic agents targeting TA systems, we believe that this study not only provides chemical tools for exploring the biological events relevant to TA systems but also opens a new gateway toward TB drug discovery.

中文翻译：

---

结核分枝杆菌VapC激活吻合肽的基于结构的从头设计。

毒素-抗毒素（TA）系统被认为是细菌存活的必要因素。在针对肺结核（TB）的药物开发计划中，我们发现了某些肽，它们模仿VapBC30复合物的结合，从而阻止了细菌细胞的生长并最终导致细胞死亡。在本文中，我们基于碳氢化合物装订策略优化了这些候选肽，并进行了生物体外评估。的V30-SP-8肽成功地穿透耻垢分枝杆菌细胞的膜和在（MIC最小抑制浓度抑制菌株的50％施加的杀菌活性₅₀）μM<6.25。借助来自VapBC30 TA系统的结构和生化信息结核分枝杆菌，我们建议潜在的抗菌剂，可以为建立新的抗菌策略提供平台。鉴于针对TA系统的治疗药物数量有限，我们认为，这项研究不仅为探索与TA系统相关的生物学事件提供了化学工具，而且为结核病药物发现打开了新的途径。