对天然产物镰刀菌酸进行结构优化以发现新型沙门氏菌III型分泌系统抑制剂。

Structural optimization of natural product fusaric acid to discover novel T3SS inhibitors of Salmonella.

作者信息

Song Yuliang, Xu Guangsen, Li Chaoqun, Li Zhiying, Lu Chunhua, Shen Yuemao

机构信息

Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.

出版信息

Biochem Biophys Res Commun. 2021 Dec 10;582:72-76. doi: 10.1016/j.bbrc.2021.10.035. Epub 2021 Oct 18.

DOI:10.1016/j.bbrc.2021.10.035

PMID:34695753

Abstract

Type III secretion system (T3SS) plays a critical role in host cell invasion and pathogenesis of Salmonella. We recently identified the mycotoxin fusaric acid (FA) as a T3SS inhibitor of Salmonella. Herein, twenty-two diphenylsulfane derivatives were designed and synthesized using FA as a lead compound through scaffold hopping. Among them, SL-8 and SL-19 possessing strong anti-T3SS and anti-invasion activity were identified as T3SS inhibitors with improvement in potency as compared to FA. The inhibitory mechanisms on SPI-1 did not depend on the HilD-HilC-RtsA-HilA or PhoP-PhoQ pathway or the assembly of T3SS needle complex. Accordingly, we proposed that the inhibitory effects of SL-8 and SL-19 on SPI-1 probably influence the formation of SicA/InvF-effector complex or other related proteins.

摘要

III型分泌系统（T3SS）在沙门氏菌侵袭宿主细胞和发病机制中起着关键作用。我们最近鉴定出霉菌毒素腐马酸（FA）是沙门氏菌的一种T3SS抑制剂。在此，以FA为先导化合物，通过骨架跃迁设计并合成了二十二种二苯硫醚衍生物。其中，具有强抗T3SS和抗侵袭活性的SL-8和SL-19被鉴定为T3SS抑制剂，与FA相比，其效力有所提高。对SPI-1的抑制机制不依赖于HilD-HilC-RtsA-HilA或PhoP-PhoQ途径，也不依赖于T3SS针状复合物的组装。因此，我们推测SL-8和SL-19对SPI-1的抑制作用可能影响SicA/InvF-效应器复合物或其他相关蛋白的形成。