School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
J Med Chem. 2021 Dec 9;64(23):17326-17345. doi: 10.1021/acs.jmedchem.1c01407. Epub 2021 Nov 30.
Herein, we report the design and synthesis of inhibitors of () 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 MurX and potent activity against . 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 growth in macrophages where mycobacteria reside and reduced mycobacterial burden in an zebrafish model of tuberculosis.
在此，我们报告了 （）磷酸-MurNAc-五肽转位酶 I（MurX）抑制剂的设计和合成，MurX 是肽聚糖合成的第一个膜相关步骤，利用了 sansanmycin 家族尿嘧啶肽天然产物的特权结构。生成了许多带有对天然产物支架假肽末端进行疏水酰胺修饰的类似物，这些类似物对 MurX 具有纳摩尔抑制活性和对 的有效活性。我们表明，带有附加的新戊酰胺部分的先导类似物具有快速抗分枝杆菌作用，其作用模式与一线抗结核药物异烟肼相似。该分子还能够抑制分枝杆菌在巨噬细胞中生长，并且在结核分枝杆菌的 斑马鱼模型中降低了分枝杆菌的负担。
