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.

There is great interest in developing antagonists of FimH, the type 1 pilus lectin displayed on the surface of uropathogenic E. coli (UPEC), for the clin. treatment of urinary tract infections (UTIs), as FimH is an essential virulence factor in UPEC pathogenesis.Addnl., with the prevalence of antibiotic resistance on the rise, targeting the FimH lectin provides an alternative therapeutic approach to the traditional antibiotic regiment for the treatment of UTIs.Already, our lab has made great strides in the development of orally available, small-mol., biaryl mannosides, as potent antagonists of the bacterial FimH lectin.Using structure-guided drug design, we have recently discovered a new class of C-mannosides, showing excellent potency against bacterial infection by UPEC, and displaying affinities one-million times greater than the mannosylated uroplakin proteins that reside on the luminal surface of the human bladder.Herein, we report on the synthesis and development of previously unexplored classes of biaryl mannoside analogs, each designed to mimic the FimH-bound conformation of our previously established lead mannosides.These new bioisosteres offer the promise of increased oral bioavailability, metabolic stability, a longer half-life, and better drug-like properties for a longer-acting biol. effect.Early preliminary results from many of these new compounds have already shown great promise in their ability to inhibit hemagglutination (HA) and biofilm formation of UPEC.We anticipate that the success of these first-in-class mannosides will ultimately lead to a widely applicable, antibiotic-sparing, therapeutic approach, one that aims to ′disarm,′ instead of kill bacteria.