Lookup NU author(s): Professor Alastair Hawkins
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The shikimic acid pathway is essential to many pathogens but absent in mammals. Enzymes in its pathway are therefore appropriate targets for the development of novel antibiotics. Dehydroquinase is the third enzyme of the pathway, catalyzing the reversible dehydratation of 3-dehydroquinic acid to form 3-dehydroshikimic acid. Here we present the synthesis of novel inhibitors with high affinity for Helicobacter pylori type II dehydroquinase and efficient inhibition characteristics. The structure of Helicobacter pylori type II dehydroquinase in complex with the most potent inhibitor shows that the aromatic functional group interacts with the catalytic Tyr22 by π-stacking, expelling the Arg17 side chain, which is essential for catalysis, from the active site. The structure therefore explains the favorable properties of the inhibitor and will aid in design of improved antibiotics.
Author(s): Prazeres VF, Tizón L, Otero JM, Guardado-Calco P, Llamas-Saiz AL, van Raaij MJ, Castedo L, Lamb H, Hawkins AR, González-Bello C
Publication type: Article
Journal: Journal of Medicinal Chemistry
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
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