State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals, Guizhou University, Guizhou 550025, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Med Chem. 2020 Aug 13;63(15):8442-8457. doi: 10.1021/acs.jmedchem.0c00803. Epub 2020 Jul 17.
Sortase A (SrtA) anchors surface proteins to the cell wall envelope, and it has attracted increasing interesting as a potential antivirulence target. Several small-molecule inhibitors for SrtA have been developed, but target validation remains largely underexplored. Herein, we report a new class of SrtA inhibitors that supports antivirulence therapy through small-molecule targeting of SrtA. Tideglusib (), a drug candidate for myotonic dystrophy, was outstanding in high-throughput screening. A concise synthetic route quickly provided analogues, and the structure-activity relationships for SrtA inhibition have been established from those analogues. Several compounds largely retained the potency and exhibited a better solubility than . Additionally, attenuated virulence-related phenotypes and protected mice against lethal USA300 bacteremia. Our study indicates that and its analogues could be new candidates as SrtA inhibitors with potential in the development of new antivirulence agents.
Sortase A (SrtA) 将表面蛋白锚定在细胞壁包膜上，它作为一种潜在的抗毒力靶标引起了越来越多的关注。已经开发出几种 SrtA 的小分子抑制剂，但靶标验证在很大程度上仍未得到充分探索。本文报道了一类新型 SrtA 抑制剂，通过小分子靶向 SrtA 支持抗毒力治疗。替度鲁肽 ()，一种肌萎缩性侧索硬化症的候选药物，在高通量筛选中表现出色。简洁的合成路线快速提供了类似物，并从这些类似物中建立了 SrtA 抑制的构效关系。几种化合物在很大程度上保留了 的活性，并且比 具有更好的溶解度。此外， 减弱了与毒力相关的表型，并保护了感染致死性 USA300 菌血症的小鼠。我们的研究表明， 和它的类似物可能是新的 SrtA 抑制剂候选物，具有开发新的抗毒力药物的潜力。
