Kang Sung-Min, Moon Heejo, Han Sang-Woo, Kim Do-Hee, Kim Byeong Moon, Lee Bong-Jin
The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
ACS Chem Biol. 2020 Sep 18;15(9):2493-2498. doi: 10.1021/acschembio.0c00492. Epub 2020 Sep 9.
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 evaluations. The peptide successfully penetrated cell membranes and exerted bactericidal activity at a minimum inhibitory concentration that inhibited 50% of the isolates (MIC) < 6.25 μM. With the aid of structural and biochemical information for the VapBC30 TA system from , 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.
毒素-抗毒素（TA）系统被认为是细菌生存的关键因素。在我们针对结核病（TB）的药物研发项目中，我们发现了某些模拟VapBC30复合物结合的肽段，这些肽段可导致细菌细胞生长停滞并最终导致细胞死亡。在此，我们基于烃链订书策略优化了这些候选肽段并进行了生物学评估。该肽成功穿透细胞膜，并在抑制50%分离株的最低抑菌浓度（MIC）<6.25μM时发挥杀菌活性。借助来自[具体来源]的VapBC30 TA系统的结构和生化信息，我们提出了潜在的抗菌剂，可为建立新型抗菌策略提供一个平台。鉴于靶向TA系统的治疗药物数量有限，我们相信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，也为结核病药物发现开辟了新途径。
