In general, the druggability of lectins (the likelihood of being able to modulate a lectin with a small-molecule drug) is considered to be low. Thus, lectins are still carelessly neglected regarding their therapeutic potential. Using the specific example of the bacterial lectin FimH, we therefore challenged the various pharmacodynamic and pharmacokinetic drawbacks associated with carbohydrate-lectin interactions. FimH is an adhesin involved in urinary tract infections (UTIs), which are primarily caused by uropathogenic Escherichia coli (UPEC). UTIs affect millions of people each year, and account for significant morbidity and high medical costs. These infections are initiated by adhesion of the lectin FimH, located at the tip of bacterial type 1 pili, to oligomannosides of the glycoprotein uroplakin 1A on bladder endothelial cells. Since bacterial resistance to antibiotics is a major problem of recurrent infections, the blocking of bacterial adhesion with soluble carbohydrates or analogs thereof is regarded as a promising therapeutic approach to UTIs. In a detailed analysis, the contributions to binding of various FimH antagonists were analyzed by X-ray, ITC and NMR, leading to a detailed understanding of the binding process. In addition, pharmacokinetic properties were optimized according to the requirements for oral administration. Finally, the most promising candidate was validated in an in vivo disease model, demonstrating its high therapeutic potential for the prevention and/or therapy of UTIs.

Druggability of lectins, using the example of a bacterial adhesin

249th National Meeting (2015)

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