FimH antagonists - solubility vs. permeability

Pang, Lijuan and Bezençon, Jacqueline and Kleeb, Simon and Rabbani, Said and Sigl, Anja and Smiesko, Martin and Sager, Christoph P. and Eris, Deniz and Schwardt, Oliver and Ernst, Beat. (2017) FimH antagonists - solubility vs. permeability. In: Carbohydrate Chemistry. London, pp. 248-273.

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Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) are among the most prevalent infections worldwide. Since frequent antibiotic treatment favors the emergence of antibiotic resistance, efficient non-antibiotic strategies are urgently needed. The first step of the pathogenesis of UTI is the bacterial adherence to urothelial host cells, a process mediated by the mannose-binding adhesin FimH located at the tip of bacterial pili. In a preliminary study, biphenyl α-d-mannopyranosides with an electron-withdrawing carboxylate on the aglycone were identified as potent FimH antagonists. Although passive permeability could be established by masking the carboxylate as an ester, insufficient solubility and fast hydrolysis did not allow to maintain the therapeutic concentration in the bladder for the requested period of time. By modifying the substitution pattern, molecular planarity and symmetry of the biphenyl aglycone could be disrupted leading to improved solubility. In addition, when heteroatoms were introduced to the aglycone, antagonists with further improved solubility, metabolic stability as well as passive permeability were obtained. The best representative, the pyrrolylphenyl mannoside 42f exhibited therapeutic urine concentration for up to 6 h and is therefore a promising oral candidate for UTI prevention and/or treatment.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Pang, Lijuan and Bezençon, Jacqueline and Kleeb, Simon and Rabbani, Said and Sigl, Anja Carina and Smiesko, Martin and Sager, Christoph and Eris, Deniz and Schwardt, Oliver
Item Type:Book Section, refereed
Book Section Subtype:Further Contribution in a Book
Publisher:Royal Society of Chemistry
Series Name:A specialist periodical report
Issue Number:42
Note:Publication type according to Uni Basel Research Database: Book item
Identification Number:
Last Modified:14 Feb 2018 14:23
Deposited On:14 Feb 2018 14:23

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