The Conformational Variability of FimH: Which Conformation Represents the Therapeutic Target?

FimH is a bacterial lectin found at the tips of type 1 pili of uropathogenic Escherichia coli (UPEC). It mediates shear-enhanced adhesion to mannosylated surfaces. Binding of UPEC to urothelial cells initiates the infection cycle leading to urinary tract infections (UTIs).

FimH antagonists: bioisosteres to improve the in vitro and in vivo PK/PD profile.

Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), belong to the most prevalent infectious diseases worldwide. The attachment of UPEC to host cells is mediated by FimH, a mannose-binding adhesin at the tip of bacterial type 1 pili. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials.

In vivo evaluation of FimH antagonists - a novel class of antimicrobials for the treatment of urinary tract infection.

The discovery of antimicrobials as β-lactam antibiotics or aminoglycosides revolutionized the treatment of infectious diseases. However, the extensive use rapidly created the problem of resistant pathogens, which are increasingly difficult to treat. FimH antagonists are a new class of antimicrobials, which target the bacterial adhesion to urothelial cells, a crucial first step in the establishment of urinary tract infections.

Antiadhesion therapy for urinary tract infections--a balanced PK/PD profile proved to be key for success.

The initial step for the successful establishment of urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli, is the adhesion of bacteria to urothelial cells. This attachment is mediated by FimH, a mannose-binding adhesin, which is expressed on the bacterial surface. To date, UTIs are mainly treated with antibiotics, leading to the ubiquitous problem of increasing resistance against most of the currently available antimicrobials.

Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists.

Urinary tract infection (UTI) caused by uropathogenic Escherichia coli (UPEC) is one of the most prevalent infectious diseases. Particularly affected are women, who have a 40-50% risk to experience at least one symptomatic UTI episode at some time during their life. In the initial step of the infection, the lectin FimH, located at the tip of bacterial pili, interacts with the high-mannosylated uroplakin Ia glycoprotein on the urinary bladder mucosa.

A flow cytometry-based assay for screening FimH antagonists.

Urinary tract infections (UTIs), including cystitis and pyelonephritis, affect a large proportion of the population and account for significant medical costs. In more than 80% of UTIs, uropathogenic Escherichia coli (UPEC) is the causative pathogen. The initial step in the pathogenesis of the infection is the adherence of UPEC to the human bladder epithelium, enabling the invasion into the host cells and the development of UTIs.

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

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.

Development of an aggregation assay to screen FimH antagonists.

Alpha-D-mannopyranosides are potent FimH antagonists, which inhibit the adhesion of Escherichia coli to highly mannosylated uroplakin Ia on the urothelium and therefore offer an efficient therapeutic opportunity for the treatment and prevention of urinary tract infection. For the evaluation of the therapeutic potential of FimH antagonists, their effect on the disaggregation of E. coli from Candida albicans and guinea pig erythrocytes (GPE) was studied.