title: FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation.
abstract: 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.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Klein
authors.forename: Daniela
authors.initials: D
authors.lastname: Abgottspon
authors.forename: Matthias
authors.initials: M
authors.lastname: Wittwer
authors.forename: Said
authors.initials: S
authors.lastname: Rabbani
authors.forename: Janno
authors.initials: J
authors.lastname: Herold
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: Simon
authors.initials: S
authors.lastname: Kleeb
authors.forename: Christine
authors.initials: C
authors.lastname: Lüthi
authors.forename: Meike
authors.initials: M
authors.lastname: Scharenberg
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bezençon
authors.forename: Erich
authors.initials: E
authors.lastname: Gubler
authors.forename: Lijuan
authors.initials: L
authors.lastname: Pang
authors.forename: Martin
authors.initials: M
authors.lastname: Smiesko
authors.forename: Brian
authors.initials: B
authors.lastname: Cutting
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D018830:Adhesins, Escherichia coli; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D015169:Colony Count, Microbial; D015195:Drug Design; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007408:Intestinal Absorption; D008362:Mannosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D012995:Solubility; D001743:Urinary Bladder / Q000187:drug effects / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000187:drug effects* / Q000201:enzymology
chemical_list: D018830:Adhesins, Escherichia coli; D000900:Anti-Bacterial Agents; D001565:Benzoates; D001798:Blood Proteins; D008362:Mannosides; D011355:Prodrugs; C058769:fimH protein, E coli; C555221:methyl 3'-chloro-4'-(mannopyranosyloxy)biphenyl-4-carboxylate; D036781:Fimbriae Proteins