FimH Antagonists: Structure-Activity and Structure-Property Relationships for Biphenyl α-D-Mannopyranosides

Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
ChemMedChem (Impact Factor: 2.97). 08/2012; 7(8):1404-22. DOI: 10.1002/cmdc.201200125
Source: PubMed


Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface-adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in-docking mode to an out-docking mode, depending on the structure of the antagonist. In this communication, biphenyl α-D-mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell-free competitive binding assay, a cell-based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure-activity and structure-property relationships were established for a series of biphenyl α-D-mannosides.

Download full-text


Available from: Oliver Schwardt, Feb 06, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mannose-based FimH antagonists are considered as new therapeutics for the treatment of urinary tract infections (UTI). They prevent the adhesion of uropathogenic Escherichia coli (UPEC) to urothelial cell surfaces triggered by the lectin FimH, which is located at the tip of bacterial type 1 pili. Since all reported FimH antagonists are α-D-mannosides, they are also potential ligands of mannose receptors of the human host system. We therefore investigated the selectivity range of five FimH antagonists belonging to different compound families by comparing their affinities for FimH and eight human mannose receptors. Based on the detected selectivity range of approximately five orders of magnitude, no adverse side effects resulting from non-selective binding to the human receptors have to be expected. FimH antagonists can therefore be further considered as potential therapeutics for the treatment of UTI.
    Full-text · Article · Oct 2012 · Journal of Medicinal Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hospital-acquired bacterial infections, especially with Gram-negative pathogens, present a major threat due to the rapid spread of antibiotic-resistant strains. Targeting mechanisms of bacterial virulence has recently appeared as a promising new therapeutic paradigm. Biofilm formation is a bacterial lifestyle, which offers a survival advantage through its protective matrix against host immune defense and antibiotic treatment. Interfering with biogenesis of adhesive organelles, bacterial communication or carbohydrate-mediated adhesion as anti-biofilm strategies are reviewed.
    No preview · Article · Apr 2013 · CHIMIA International Journal for Chemistry
  • Source
    [Show abstract] [Hide abstract]
    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 (koff ) 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.
    Full-text · Article · Jan 2014 · ChemMedChem
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.