Publication Details (including relevant citation information):
Menard, R., Schoenhofen, I.C., Tai, L., Aubry, A., Bouchard, P., Reid, C.W. Lachance, P., Twine, S., Matte, A., Fulton, K., Cui, Q., Herve, H., Purisima, E.O., Sulea, T., Logan, S.M. (2014) Antimicrob Agents Chemother In Press doi: 10.1128/AAC.03858-14.
Helicobacter pylori is motile by means of polar flagella and this motility has been shown to play a critical role in pathogenicity. The major structural flagellin proteins have been shown to be glycosylated with the novel nonulosonate sugar, pseudaminic acid (Pse) and this process of glycosylation is required for flagellar assembly and consequent motility. As such, the Pse biosynthetic pathway offers considerable potential as an anti-virulence drug target and this study describes screening for small molecule inhibitors of the five Pse biosynthetic enzymes using both high throughput and in silico approaches. Following kinetic studies and SAR of selected inhibitors identified from these initial studies, we demonstrated that three inhibitors with IC50 values of approximately 14 µM and which belonged to a distinct chemical cluster, were able to penetrate the Gram negative cell membrane and prevent flagella formation.