In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Abgottspon, Daniela; Ernst, Beat

doi:10.2533/chimia.2012.166

Cited by 16 publications

(20 citation statements)

References 27 publications

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“…A particularly promising class of drugs include remedies that inhibit bacterial adhesion to urothelial cells i.e . FimH antagonists for example in the form of vaccines, which, by their mechanism of action minimize bacterial drug resistance [81–84]. Design of FimH antagonists, precisely glyco-agonists are based on the imitation of natural sugar epitope structures [63, 83, 85].…”

Section: Mannose Residues On Upia Are Pivotal For Urinary Tract Ecolmentioning

confidence: 99%

Glycosylation of uroplakins. Implications for bladder physiopathology

2014

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Urothelium, a specialized epithelium, covers the urinary tract and act not only as a barrier separating its light from the surrounding tissues, but fulfills an important role in maintaining the homeostasis of the urothelial tract and well-being of the whole organism. Proper function of urothelium is dependent on the precise assemble of highly specialized glycoproteins called uroplakins, the end products and differentiation markers of the urothelial cells. Glycosylation changes in uroplakins correlate with and might reflect progressive stages of pathological conditions of the urothelium such as cancer, urinary tract infections, interstitial cystitis and others. In this review we focus on sugar components of uroplakins, their emerging role in urothelial biology and disease implications. The advances in our understanding of uroplakins changes in glycan moieties composition, structure, assembly and expression of their glycovariants could potentially lead to the development of targeted therapies and discoveries of novel urine and plasma markers for the benefit of patients with urinary tract diseases.

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Section: Mannose Residues On Upia Are Pivotal For Urinary Tract Ecolmentioning

confidence: 99%

Glycosylation of uroplakins. Implications for bladder physiopathology

2014

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“…[28] An anti-adhesiont herapy with FimH antagonists, whichb lock the adhesion and thereby preventt he infection, could therefore be beneficialf or patients suffering from recurrent UTI. [29] Re-analyzing data from numerous ITC [30] and SPR [31] studies we published in the last 5years, enabledt he validation of the kinITC-ETC approachand the correlationo fk inetic parameters with structural properties of a large ligand dataset. The kinetic fingerprints of FimH antagonists offer the opportunity to furtheri mprove the binding characteristics essential for ac linical application.…”

Section: Introductionmentioning

confidence: 99%

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

Zihlmann

Silbermann

Sharpe

et al. 2018

Chemistry A European J

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Affinity data, such as dissociation constants (K ) or inhibitory concentrations (IC ), are widely used in drug discovery. However, these parameters describe an equilibrium state, which is often not established in vivo due to pharmacokinetic effects and they are therefore not necessarily sufficient for evaluating drug efficacy. More accurate indicators for pharmacological activity are the kinetics of binding processes, as they shed light on the rate of formation of protein-ligand complexes and their half-life. Nonetheless, although highly desirable for medicinal chemistry programs, studies on structure-kinetic relationships (SKR) are still rare. With the recently introduced analytical tool kinITC this situation may change, since not only thermodynamic but also kinetic information of the binding process can be deduced from isothermal titration calorimetry (ITC) experiments. Using kinITC, ITC data of 29 mannosides binding to the bacterial adhesin FimH were re-analyzed to make their binding kinetics accessible. To validate these kinetic data, surface plasmon resonance (SPR) experiments were conducted. The kinetic analysis by kinITC revealed that the nanomolar affinities of the FimH antagonists arise from both (i) an optimized interaction between protein and ligand in the bound state (reduced off-rate constant k ) and (ii) a stabilization of the transition state or a destabilization of the unbound state (increased on-rate constant k ). Based on congeneric ligand modifications and structural input from co-crystal structures, a strong relationship between the formed hydrogen-bond network and k could be concluded, whereas electrostatic interactions and conformational restrictions upon binding were found to have mainly an impact on k .

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“…Bacteriala dhesiona tt he cell surface takes place throughm ultivalentp rotein-carbohydrate interactions betweent he bacterial proteins (e.g.,t oxins, adhesins, and lectins) and the glycoconjugates at the outer cell membrane (e.g.,g lycolipids and glycoproteins). [1] High avidity is achieved throughm ultivalency by presenting multiple copieso ft he oligosaccharidic partner at the malleable cell surface and also by the multimeric character of most bacterial lectins.T he design of synthetic analogues of oligosaccharides hasb een largely studied by chemists [2,3] and has now providedi nteresting results in antiadhesivetherapy against bacterial infectionst hat target, for instance, Escherichia coli [4][5][6][7][8] or Pseudomonas aeruginosa. [9][10][11][12][13][14] LecA andL ecB are two soluble tetrameric lectinso fPseudomonas aeruginosa implicated in biofilm formation.…”

Section: Introductionmentioning

confidence: 99%

Toward the Rational Design of Galactosylated Glycoclusters That Target Pseudomonas aeruginosa Lectin A (LecA): Influence of Linker Arms That Lead to Low‐Nanomolar Multivalent Ligands

Wang

Dupin

Noël

et al. 2016

Chemistry A European J

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Anti-infectious strategies against pathogen infections can be achieved through antiadhesive strategies by using multivalent ligands of bacterial virulence factors. LecA and LecB are lectins of Pseudomonas aeruginosa implicated in biofilm formation. A series of 27 LecA-targeting glycoclusters have been synthesized. Nine aromatic galactose aglycons were investigated with three different linker arms that connect the central mannopyranoside core. A low-nanomolar (Kd =19 nm, microarray) ligand with a tyrosine-based linker arm could be identified in a structure-activity relationship study. Molecular modeling of the glycoclusters bound to the lectin tetramer was also used to rationalize the binding properties observed.

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In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Cited by 16 publications

References 27 publications

Glycosylation of uroplakins. Implications for bladder physiopathology

Glycosylation of uroplakins. Implications for bladder physiopathology

KinITC—One Method Supports both Thermodynamic and Kinetic SARs as Exemplified on FimH Antagonists

Toward the Rational Design of Galactosylated Glycoclusters That Target Pseudomonas aeruginosa Lectin A (LecA): Influence of Linker Arms That Lead to Low‐Nanomolar Multivalent Ligands

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