Dey Supratim, Anbanandam Asokan, Mumford Ben E, De Guzman Roberto N
Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS, 66045, USA.
Current address: Center for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Blvd., Suite #303, Tampa, FL, 33612, USA.
ChemMedChem. 2017 Sep 21;12(18):1534-1541. doi: 10.1002/cmdc.201700348. Epub 2017 Aug 31.
Many pathogens such as Shigella and other bacteria assemble the type III secretion system (T3SS) nanoinjector to inject virulence proteins into their target cells to cause infectious diseases in humans. The rise of drug resistance among pathogens that rely on the T3SS for infectivity, plus the dearth of new antibiotics require alternative strategies in developing new antibiotics. The Shigella T3SS tip protein IpaD is an attractive target for developing anti-infectives because of its essential role in virulence and its exposure on the bacterial surface. Currently, the only known small molecules that bind to IpaD are bile salt sterols. In this study we identified four new small-molecule scaffolds that bind to IpaD, based on the methylquinoline, pyrrolidine-aniline, hydroxyindole, and morpholinoaniline scaffolds. NMR mapping revealed potential hotspots in IpaD for binding small molecules. These scaffolds can be used as building blocks in developing small-molecule inhibitors of IpaD that could lead to new anti-infectives.
许多病原体，如志贺氏菌和其他细菌，会组装III型分泌系统（T3SS）纳米注射器，将毒力蛋白注入靶细胞，从而在人类中引发传染病。依赖T3SS进行感染的病原体中耐药性的增加，加上新抗生素的匮乏，需要开发新抗生素的替代策略。志贺氏菌T3SS顶端蛋白IpaD因其在毒力中的关键作用以及在细菌表面的暴露，是开发抗感染药物的一个有吸引力的靶点。目前，已知的唯一与IpaD结合的小分子是胆盐固醇。在本研究中，我们基于甲基喹啉、吡咯烷 - 苯胺、羟基吲哚和吗啉代苯胺支架，鉴定出四种与IpaD结合的新小分子支架。核磁共振图谱揭示了IpaD中与小分子结合的潜在热点。这些支架可作为开发IpaD小分子抑制剂的基础材料，有望带来新的抗感染药物。
