Bivalent Inhibitors of Mannose‐specific Bacterial Adhesion: A Xylose‐Based Conformational Switch to Control Glycoligand Distance

Functional glycomimetics are suited to study the parameters of carbohydrate recognition that forms the basis of glycobiology. It is particularly attractive when a glycoligand allows for the investigation of two different states, such as varying distance between multiple glycoligands. Here, a xylopyranoside has been employed as a scaffold for the presentation of two mannoside units which are ligands of the bacterial lectin FimH. The chair conformation of the central xyloside can be switched between a 4C1 and a 1C4 conformation whereby the two conjugated mannoside ligands are flipped from a di-equatorial into a di-axial position. Concomitantly the distance between the two glycoligands changes and as a consequence also the biological activity of the respective bivalent glycocluster, as shown in adhesion-inhibition assays with live bacteria. Molecular modeling was employed to correlate the inter-ligand distance with the structure of the formed glycocluster-FimH complex. Our study suggests that conformational switches can be employed and further advanced as smart molecular tools to study structural boundary conditions of carbohydrate recognition in a bottom-up approach.