美国德克萨斯农工大学James C. Sacchettini团队发现，天然产物衍生的sequanamycin可作为有效的口服抗结核药物。2023年2月23日，国际知名学术期刊《细胞》在线发表了这一成果。
研究人员报告了一系列被称为sequanamycin的大环内酯类化合物，它们在体外和体内对结核分枝杆菌（Mtb）具有显著的活性。sequanamycin是一种细菌核糖体抑制剂，与核糖体相互作用的方式与经典大环内酯类药物（如红霉素和克拉霉素）类似，但具有结合特性，使它们能够克服结核分枝杆菌固有的大环内酯类耐药性。结合抑制剂的核糖体结构被用于优化sequanamycin，进而生产先进的先导化合物SEQ-9。SEQ-9在急性和慢性结核模型中作为单一药物有效，并在小鼠结核感染模型中与其他结核药物联合使用显示出杀菌活性。这些结果支持进一步研究该系列作为结核病临床候选药物，并有可能成为治疗药物敏感和耐药结核病的新方案。
据介绍，耐药结核病的出现迫切需要新的抗结核药物。
附：英文原文
Title: Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents
Author: Jidong Zhang, Christine Lair, Christine Roubert, Kwame Amaning, María Belén Barrio, Yannick Benedetti, Zhicheng Cui, Zhongliang Xing, Xiaojun Li, Scott G. Franzblau, Nicolas Baurin, Florence Bordon-Pallier, Cathy Cantalloube, Stephanie Sans, Sandra Silve, Isabelle Blanc, Laurent Fraisse, Alexey Rak, Lasse B. Jenner, Gulnara Yusupova, Marat Yusupov, Junjie Zhang, Takushi Kaneko, T.J. Yang, Nader Fotouhi, Eric Nuermberger, Sandeep Tyagi, Fabrice Betoudji, Anna Upton, James C. Sacchettini, Sophie Lagrange
Issue&Volume: 2023-02-23
Abstract: The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.
DOI: 10.1016/j.cell.2023.01.043
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00102-2