par Touaibia, Mohamed;Krammer, Eva-Maria ;Shiao, Tze TC;Yamakawa, Nao;Wang, Qingan;Glinschert, Anja;Papadopoulos, Alex;Mousavifar, Leila;Maes, Emmanuel;Oscarson, Stefan;Vergoten, Gerard;Lensink, M F;Roy, René;Bouckaert, Julie
Référence Molecules, 22, 7
Publication Publié, 2017
Référence Molecules, 22, 7
Publication Publié, 2017
Article révisé par les pairs
Résumé : | Antagonists of the Escherichia coli type-1 fimbrial adhesin FimH are recognized as attractive alternatives for antibiotic therapies and prophylaxes against acute and recurrent bacterial infections. In this study α-d-mannopyranosides O- or C-linked with an alkyl, alkene, alkyne, thioalkyl, amide, or sulfonamide were investigated to fit a hydrophobic substituent with up to two aryl groups within the tyrosine gate emerging from the mannose-binding pocket of FimH. The results were summarized into a set of structure-activity relationships to be used in FimH-targeted inhibitor design: alkene linkers gave an improved affinity and inhibitory potential, because of their relative flexibility combined with a favourable interaction with isoleucine-52 located in the middle of the tyrosine gate. Of particular interest is a C-linked mannoside, alkene-linked to an ortho-substituted biphenyl that has an affinity similar to its O-mannosidic analog but superior to its para-substituted analog. Docking of its high-resolution NMR solution structure to the FimH adhesin indicated that its ultimate, ortho-placed phenyl ring is able to interact with isoleucine-13, located in the clamp loop that undergoes conformational changes under shear force exerted on the bacteria. Molecular dynamics simulations confirmed that a subpopulation of the C-mannoside conformers is able to interact in this secondary binding site of FimH. |