Kinetic Properties of Carbohydrate–Lectin Interactions: FimH Antagonists

Abstract

The lectin FimH is terminally expressed on type 1 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 (t₁/₂) of the FimH antagonist complexes are above 3.6 h. For a therapeutic application, extended t₁/₂ values are a prerequisite for success, since the target occupancy time directly influences the in vivo drug efficacy. The long t₁/₂ value of the tested FimH antagonists further confirms their drug-like properties and their high therapeutic potential.

Cinnamide Derivatives of d -Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa

“…Methyl mannoside ( 1 ), sulfonamide 2 , cinnamide 3, and its derivative 7 b , which showed the highest potency among the cinnamide series in LecB inhibition, were analyzed by SPR (Figure , Table ). Unmodified mannoside 1 showed fast binding kinetics, which are usually observed with lectin–carbohydrate interactions . The measured K d of 47 μ m was in good agreement with the previously determined thermodynamic value of 71 μ m by ITC .…”

“…Unmodified mannoside 1 showed fast binding kinetics, which are usually observed with lectin-carbohydrate interactions. [31] The measured K d of 47 mm was in good agreement with the previously determined thermodynamic value of 71 mm by ITC. [26] Sulfonamide 2 showedatwo-fold highero n rate and av ery slow off rate of 6.2 10 À4 s À1 .T he half-life (t 1/2 = ln2/k off )o ft he complex of LecB and sulfonamide 2 was 18.6 min, explaining its very high affinity (K d = 1.12 mm by SPR, 3.3 mm [25] by ITC) towards LecB compared to at 1/2 of only 45 sf or 1.I ti s important to note, that long drug-receptor half lives are important for in vivo functiona nd future success for drug development.…”

The Tyrosine Gate of the Bacterial Lectin FimH: A Conformational Analysis by NMR Spectroscopy and X‐ray Crystallography

“…The observation is in accordance with nanomolar to low micromolar affinities (Table 2) andw ith kinetic data obtained from surfacep lasmon resonance experiments. [32] Interestingly,e ven antagonist 11, which binds to FimH-CRD with ag reatlyd iminished affinity of 83 mm (Table 2), was found to be in slow or intermediate exchange. Slow exchange kinetics might suggest rearrangements of conformation during complex formation.…”

En route from artificial to natural: Evaluation of inhibitors of mannose-specific adhesion of E. coli under flow

“…[8,9,30,31,34] Compared with other reliable testing methods like hemagglutination assays or surface plasmon resonance, our assay showed similar inhibition properties for the investigated mannosides. [35,36] …”