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

Möckl, Leonhard; Fessele, Claudia; Despras, Guillaume; Bräuchle, Christoph

doi:10.1016/j.bbagen.2016.06.021

Cited by 5 publications

(4 citation statements)

References 42 publications

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“…Instead, we propose that the increased affinity is related to each linker's chemical nature and impact on the binding energetics. This phenomenon has been observed with similar monovalent ligands, which were used as FimH antagonists and showed the same trend . Depending on the chemical nature of the aglycone moiety, more or less favorable additional interactions were formed with the lectin's carbohydrate binding site, an explanation which could be rationalized by docking studies .…”

Section: Resultssupporting

confidence: 71%

Linear Precision Glycomacromolecules with Varying Interligand Spacing and Linker Functionalities Binding to Concanavalin A and the Bacterial Lectin FimH

Igde

Röblitz

Müller

et al. 2017

Macromolecular Bioscience

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A series of precision glycomacromolecules is prepared following previously established solid phase synthesis allowing for controlled variations of interligand spacing and the overall number of carbohydrate ligands. In addition, now also different linkers are installed between the carbohydrate ligand and the macromolecular scaffold. The lectin binding behavior of these glycomacromolecules is then evaluated in isothermal titration calorimetry (ITC) and kinITC experiments using the lectin Concanavalin A (Con A) in its dimeric and tetrameric form. The results indicate that both sterical and statistical effects impact lectin binding of precision glycomacromolecules. Moreover, ITC results show that highest affinity toward Con A can be achieved with an ethyl phenyl linker, which parallels earlier findings with the bacterial lectin FimH. In this way, a first set of glycomacromolecule structures is selected for testing in a bacterial adhesion-inhibition study. Here, the findings point to a one-sugar binding mode mainly affected by sterical restraints of the nonbinding parts of the respective glycomacromolecule.

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Section: Resultssupporting

confidence: 71%

Linear Precision Glycomacromolecules with Varying Interligand Spacing and Linker Functionalities Binding to Concanavalin A and the Bacterial Lectin FimH

Igde

Röblitz

Müller

et al. 2017

Macromolecular Bioscience

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“…This indicated that the interactions between FimH and mannosefunctionalized nanoparticles were weaker than those between FimH and mannose monomers. This result is in agreement with the inhibition potency of mannosides with respect to the adhesion of E. coli to mannose-coated surfaces [40]. It has also been proven that the binding between mannosecontaining magnetic nanoparticles is highly specific, which could be effective for the immobilization of E. coli.…”

Section: Characterization Of the Nanoparticlessupporting

confidence: 88%

Specific Immobilization of Escherichia coli Expressing Recombinant Glycerol Dehydrogenase on Mannose-Functionalized Magnetic Nanoparticles

Zhuang

Shen

et al. 2018

Catalysts

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Mannose-functionalized magnetic nanoparticles were prepared for the immobilization of Escherichia coli cells harboring the recombinant glycerol dehydrogenase gene. Immobilization of whole E. coli cells on the carrier was carried out through specific binding between mannose on the nanoparticles and the FimH lectin on the E. coli cell surface via hydrogen bonds and hydrophobic interactions. The effects of various factors including cell concentration, pH, temperature, and buffer concentration were investigated. High degrees of immobilization (84%) and recovery of activity (82%) were obtained under the following conditions: cell/support 1.3 mg/mL, immobilization time 2 h, pH 8.0, temperature 4°C, and buffer concentration 50 mM. Compared with the free cells, the thermostability of the immobilized cells was improved 2.56-fold at 37 °C. More than 50% of the initial activity of the immobilized cells remained after 10 cycles. The immobilized cells were evaluated functionally by monitoring the catalytic conversion of glycerol to 1,3-dihydroxyacetone (DHA). After a 12 h reaction, the DHA produced by the immobilized cells was two-fold higher than that produced by the free cells. These results indicate that mannose-functionalized magnetic nanoparticles can be used for the specific recognition of gram-negative bacteria, which gives them great potential in applications such as the preparation of biocatalysts and biosensors and clinical diagnosis.

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“…It has also been shown that mannosides can bind with different affinities under “flow” or “non-flow” conditions as determined from in vitro assays [95-97]. Taken together, further studies are necessary to (a) determine the role of shear stress on pathogenicity in vivo and (b) assess the SAR and selectivity of many diverse mannosides toward these two conformations.…”

Section: X-ray Structure Guided Design Of Monovalent O-mannoside mentioning

confidence: 99%

Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

Mydock-McGrane

Hannan

Janetka

2017

Expert Opinion on Drug Discovery

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Introduction The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn's Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection. Areas covered The authors describe the structure-guided design of mannoside ligands, and review the structural biology of the FimH lectin domain. Additionally, they discuss the lead optimization of mannosides for therapeutic application in UTI and CD, and describe various assays used to measure mannoside potency in vitro and mouse models used to determine efficacy in vivo. Expert opinion To date, mannoside optimization has led to a diverse set of small-molecule FimH antagonists with oral bioavailability. With clinical trials already initiated in CD and on the horizon for UTI, it is the authors opinion that mannosides will be a ‘first-in-class’ treatment strategy for UTI and CD, and will pave the way for treatment of other Gram-negative bacterial infections.

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

Cited by 5 publications

References 42 publications

Linear Precision Glycomacromolecules with Varying Interligand Spacing and Linker Functionalities Binding to Concanavalin A and the Bacterial Lectin FimH

Linear Precision Glycomacromolecules with Varying Interligand Spacing and Linker Functionalities Binding to Concanavalin A and the Bacterial Lectin FimH

Specific Immobilization of Escherichia coli Expressing Recombinant Glycerol Dehydrogenase on Mannose-Functionalized Magnetic Nanoparticles

Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

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