Christopher Reid - Small-molecule inhibitors of the pseudominic acid biosynthetic pathway: targeting motility as a key bacterial virulence factor

Document created by Christopher Reid on Oct 16, 2014
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  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. 

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