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Article Dans Une Revue Molecules Année : 2017

Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin

Mohamed Touaibia
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Stefan Oscarson

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
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hal-02389369 , version 1 (14-02-2024)

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Mohamed Touaibia, Eva-Maria Krammer, Tze Shiao, Nao Yamakawa, Qingan Wang, et al.. Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin. Molecules, 2017, 22 (7), pp.1101. ⟨10.3390/molecules22071101⟩. ⟨hal-02389369⟩

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