Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against Mtb MurX and potent activity against Mtb in vitro. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.

中文翻译：

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作为有效的结核分枝杆菌转位酶 I 抑制剂的合成三三霉素类似物

在这里，我们报告了结核分枝杆菌( Mtb ) 磷酸-MurNAc-五肽转位酶 I (MurX) 抑制剂的设计和合成，这是肽聚糖合成的第一个膜相关步骤，利用了尿苷肽天然产物三三霉素家族的特权结构。产生了许多对天然产物支架的假肽末端进行疏水酰胺修饰的类似物，它们在体外表现出对Mtb MurX 的纳摩尔抑制活性和对 Mtb 的有效活性. 我们表明，带有附加新戊酰胺部分的铅类似物具有快速的抗分枝杆菌作用，其特征类似于一线结核病药物异烟肼。该分子还能够抑制体内分枝杆菌存在的巨噬细胞中的Mtb生长，并减少体内斑马鱼结核病模型中的分枝杆菌负担。