Abstract：
Drug-resistant Mycobacterium tuberculosis (Mtb) remains a major public health concern requiring complementary approaches to standard anti-tuberculous regimens. Anti-virulence molecules or compounds that enhance the activity of antimicrobial prodrugs are promising alternatives to conventional antibiotics. Exploiting host cell-based drug discovery, we identified an oxadiazole compound (S3) that blocks the ESX-1 secretion system, a major virulence factor of Mtb. S3-treated mycobacteria showed impaired intracellular growth and a reduced ability to lyse macrophages. RNA sequencing experiments of drug-exposed bacteria revealed strong upregulation of a distinct set of genes including ethA, encoding a monooxygenase activating the anti-tuberculous prodrug ethionamide. Accordingly, we found a strong ethionamide boosting effect in S3-treated Mtb. Extensive structure-activity relationship experiments revealed that anti-virulence and ethionamide-boosting activity can be uncoupled by chemical modification of the primary hit molecule. To conclude, this series of dual-active oxadiazole compounds targets Mtb via two distinct mechanisms of action.
摘要：
耐药结核分枝杆菌（Mtb）仍然是一个主要的公共卫生问题，需要对标准抗结核方案采取补充方法。增强抗微生物前药活性的抗毒性分子或化合物是常规抗生素的有希望的替代品。利用基于宿主细胞的药物发现，我们确定了一种阻断ESX-1分泌系统的恶二唑化合物（S3），Mtb的主要毒力因子。S3处理的分枝杆菌显示细胞内生长受损和裂解巨噬细胞的能力降低。暴露于药物的细菌的RNA测序实验显示，包括ethA在内的一组不同基因的强烈上调，编码激活抗结核前药乙硫酰胺的单加氧酶。因此，我们在S3治疗的Mtb中发现了很强的乙二甲酰胺增强作用。广泛的结构-活性关系实验表明，可以通过对初级命中分子进行化学修饰来分离抗毒力和乙硫氨酰胺增强活性。最后，这一系列双重活性恶二唑化合物通过两种不同的作用机制靶向Mtb。
