| FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. | |
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MedLine Citation:
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PMID: 21105658 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Urinary tract infection (UTI) by uropathogenic Escherichia coli (UPEC) is one of the most common infections, particularly affecting women. The interaction of FimH, a lectin located at the tip of bacterial pili, with high mannose structures is critical for the ability of UPEC to colonize and invade the bladder epithelium. We describe the synthesis and the in vitro/in vivo evaluation of α-D-mannosides with the ability to block the bacteria/host cell interaction. According to the pharmacokinetic properties, a prodrug approach for their evaluation in the UTI mouse model was explored. As a result, an orally available, low molecular weight FimH antagonist was identified with the potential to reduce the colony forming units (CFU) in the urine by 2 orders of magnitude and in the bladder by 4 orders of magnitude. With FimH antagonist, the great potential for the effective treatment of urinary tract infections with a new class of orally available antiinfectives could be demonstrated. |
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Authors:
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Tobias Klein; Daniela Abgottspon; Matthias Wittwer; Said Rabbani; Janno Herold; Xiaohua Jiang; Simon Kleeb; Christine Lüthi; Meike Scharenberg; Jacqueline Bezençon; Erich Gubler; Lijuan Pang; Martin Smiesko; Brian Cutting; Oliver Schwardt; Beat Ernst |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-24 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 53 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-17 Completed Date: 2011-01-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 8627-41 Citation Subset: IM |
Affiliation:
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Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adhesins, Escherichia coli Administration, Oral Animals Anti-Bacterial Agents / chemical synthesis*, pharmacokinetics, pharmacology Benzoic Acids / chemical synthesis*, pharmacokinetics, pharmacology Binding, Competitive Blood Proteins / metabolism Caco-2 Cells Cell Membrane Permeability Colony Count, Microbial Drug Design Escherichia coli Infections / drug therapy*, microbiology Female Fimbriae Proteins / antagonists & inhibitors* Host-Pathogen Interactions / drug effects Humans Intestinal Absorption Mannosides / chemical synthesis*, pharmacokinetics, pharmacology Mice Prodrugs / chemical synthesis*, pharmacokinetics, pharmacology Protein Binding Solubility Urinary Bladder / drug effects, microbiology Urinary Tract Infections / drug therapy*, microbiology Uropathogenic Escherichia coli / drug effects*, enzymology |
| Chemical | |
Reg. No./Substance:
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0/Adhesins, Escherichia coli; 0/Anti-Bacterial Agents; 0/Benzoic Acids; 0/Blood Proteins; 0/Mannosides; 0/Prodrugs; 0/fimH protein, E coli; 0/methyl 3'-chloro-4'-(mannopyranosyloxy)biphenyl-4-carboxylate; 147680-16-8/Fimbriae Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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