FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation

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

doi:10.1021/jm101011y

FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation

J Med Chem. 2010 Dec 23;53(24):8627-41. doi: 10.1021/jm101011y. Epub 2010 Nov 24.

Authors

Tobias Klein¹, 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

Affiliation

¹ Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.

PMID: 21105658
DOI: 10.1021/jm101011y

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adhesins, Escherichia coli
Administration, Oral
Animals
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacokinetics
Anti-Bacterial Agents / pharmacology
Benzoates / chemical synthesis*
Benzoates / pharmacokinetics
Benzoates / pharmacology
Binding, Competitive
Blood Proteins / metabolism
Caco-2 Cells
Cell Membrane Permeability
Colony Count, Microbial
Drug Design
Escherichia coli Infections / drug therapy*
Escherichia coli Infections / microbiology
Female
Fimbriae Proteins / antagonists & inhibitors*
Host-Pathogen Interactions / drug effects
Humans
Intestinal Absorption
Mannosides / chemical synthesis*
Mannosides / pharmacokinetics
Mannosides / pharmacology
Mice
Prodrugs / chemical synthesis*
Prodrugs / pharmacokinetics
Prodrugs / pharmacology
Protein Binding
Solubility
Urinary Bladder / drug effects
Urinary Bladder / microbiology
Urinary Tract Infections / drug therapy*
Urinary Tract Infections / microbiology
Uropathogenic Escherichia coli / drug effects*
Uropathogenic Escherichia coli / enzymology

Substances

Adhesins, Escherichia coli
Anti-Bacterial Agents
Benzoates
Blood Proteins
Mannosides
Prodrugs
fimH protein, E coli
methyl 3'-chloro-4'-(mannopyranosyloxy)biphenyl-4-carboxylate
Fimbriae Proteins