Kinetic Properties of Carbohydrate-Lectin Interactions: FimH Antagonists

The lectin FimH is terminally expressed on type1 pili of uropathogenic Escherichia coli (UPEC), which is the main cause of urinary tract infections (UTIs). FimH enables bacterial adhesion to urothelial cells, the initial step of infection. Various mannose derivatives have been shown to antagonize FimH and are therefore considered to be promising therapeutic agents for the treatment of UTIs. As part of the preclinical development process, when the kinetic properties of FimH antagonists were examined by surface plasmon resonance, extremely low dissociation rates (k(off)) were found, which is uncommon for carbohydrate-lectin interactions. As a consequence, the corresponding half-lives (t(1/2)) of the FimH antagonist complexes are above 3.6h. For a therapeutic application, extended t(1/2) values are a prerequisite for success, since the target occupancy time directly influences the in vivo drug efficacy. The long t(1/2) value of the tested FimH antagonists further confirms their drug-like properties and their high therapeutic potential.