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.

耐药结核病的出现导致了对新型抗结核药物的迫切需求。在这里，我们报告了一系列称为 sequanamycins 的大环内酯类化合物的发现，它们具有出色的体外和体内抗结核分枝杆菌活性（公吨）。Sequanamycins 是细菌核糖体抑制剂，与核糖体相互作用的方式类似于红霉素和克拉霉素等经典大环内酯类药物，但具有结合特性，可以克服 Mtb 固有的大环内酯类药物耐药性。具有结合抑制剂的核糖体结构被用于优化sequanamycin以产生高级先导化合物SEQ-9。SEQ-9 作为单一药物在急性和慢性结核病小鼠模型中有效，并且它与其他结核病药物联合在小鼠结核病感染模型中表现出杀菌活性。这些结果支持进一步研究该系列作为 TB 临床候选物，并有可能用于抗药敏和耐药 TB 的新方案。