Characterization of Small Molecule Scaffolds that Bind to the Shigella Type III Secretion System Protein IpaD

This is the peer reviewed version of the following article: ChemMedChem. 2017 Sep 21; 12(18): 1534–1541., which has been published in final form at http://doi.org/10.1002/cmdc.201700348. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.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 salts sterols. Here, we identified four new small molecule scaffolds that bind to IpaD based on the methylquinoline, pyrrolidin-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