Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors
Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors
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DOI：
10.1021/acs.jmedchem.1c01407
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发表时间：
2021-12-09
影响因子：
7.3
通讯作者：
Payne, Richard J.
中科院分区：
文献类型：
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作者：
Tran, Wendy;Kusay, Ali S.;Payne, Richard J.
在此，我们报告结核分枝杆菌（Mtb）磷酸-MurNAc-五肽转位酶I（MurX）的抑制剂的设计和合成，肽聚糖合成的第一个膜相关步骤，利用尿苷肽天然产物的sansanmycin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，其在体外表现出针对Mtb MurX的纳摩尔抑制活性和针对Mtb的有效活性。我们发现，一个铅类似物轴承附加新戊酰胺部分具有快速的抗分枝杆菌的作用，与前线结核病药物异烟肼类似的配置文件。该分子还能够抑制分枝杆菌在体内驻留的巨噬细胞中的Mtb生长，并降低结核病的体内斑马鱼模型中的分枝杆菌负荷。
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.