Fimbrion Therapeutics, Inc.

The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn's Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection. Areas covered: The authors describe the structure-guided design of mannoside ligands, and review the structural biology of the FimH lectin domain. Additionally, they discuss the lead optimization of mannosides for therapeutic application in UTI and CD, and describe various assays used to measure mannoside potency in vitro and mouse models used to determine efficacy in vivo. Expert opinion: To date, mannoside optimization has led to a diverse set of small-molecule FimH antagonists with oral bioavailability. With clinical trials already initiated in CD and on the horizon for UTI, it is the authors, opinion that mannosides will be a 'first-in-class' treatment strategy for UTI and CD, and will pave the way for treatment of other Gram-negative bacterial infections.

Type 1 pili are utilized by Gram-negative bacteria to adhere to host tissue and thus are a key virulence factor in urinary tract infections (UTIs) and Crohn's disease (CD). This adhesion is mediated through specific binding of the terminal adhesin, FimH, to mannosylated host glycoproteins. FimH is essential for UTI pathogenesis and thus is a promising therapeutic target.

Herein, we review the structural frameworks of FimH antagonists disclosed in the patent literature. X-ray crystallographic binding studies of D-mannose and early FimH antagonists have uncovered key molecular interactions. Exploiting this knowledge, mannosides with extraordinarily high binding affinities have been designed. Structure-activity relationships (SAR) and structure-property relationship (SPR) studies have resulted in the rapid development of orally bioavailable FimH antagonists with promising therapeutic potential for UTI and CD.

It is our opinion that biaryl or 'two-ring' mannosides, which represent the largest and most thoroughly tested class of FimH antagonists, also hold the most promise as a novel treatment for UTIs. These antagonists have also been shown to have efficacy in treating CD. Judging from the strong preclinical data, we predict that one or more FimH antagonists will be entering the clinic within the next 1-2 years.

Urinary tract infections (UTIs) represent one of the largest causes of bacterial infections, with the overwhelming majority of these cases caused by uropathogenic Escherichia coli (UPEC).Due to high recurrence rates, UTIs are becoming increasingly resistant to standard antibiotic therapies, resulting in a high, unmet, medical need for the development of new strategies to combat UTIs and other Gram-neg. bacterial infections.As an alternative to traditional antibiotics, carbohydrate-based small-mols. are being developed which target and inhibit the function of specific bacterial adhesins on UPEC.This approach renders the bacteria incapable of adhering to host tissue, precluding subsequent invasion and establishment of an infection, and simultaneously circumvents the adaptive stress that accompanies the use of bactericidal agents which ultimately leads to resistance.In our current work, great progress has been made in the structure-guided development of orally bioavailable C-mannosides as antagonists of the FimH adhesin, which is located at the tip of the type 1 pilus on the surface of UPEC.FimH binds specifically to terminal mannose residues on glycopeptides which coat the bladder epithelium, and has been found necessary for the establishment of a UTI, and for the formation of intercellular bacterial communities (IBCs) and biofilms.With potencies nearly 1 million-fold greater than alpha-D-mannose, when orally dosed our C-mannosides show unparalleled ability to abrogate bacterial burdens in both acute and chronic mouse models of UTI, as well as the ability to disrupt biofilm formation.Demonstrating the general applicability of this carbohydrate-based, anti-adhesive approach to treating bacterial infections, we have also begun making strides in the development of addnl. carbohydrate-based antagonists, which have been rationally designed to target UPEC adhesins that have been further implicated in uropathogenesis, such as FmlH and F17-like (cystitis), and PapG (pyelonephritis).