Over two-thirds of the approximately 10 million urinary tract infections (UTIs) each year are caused by E. coli. The process of infection involves initial association of E. coli cells with epithelial cells in the urinary tract (urothelial cells), community formation, and delamination of urothelial cells. The communities can also invade urothelial cells, remain quiescent, and then re-appear later for recurring rounds of infection. One strategy for the treatment and prevention of UTIs is the anti-adhesin approach, where a soluble ligand is used to antagonize the E. coli:urothelial cell interaction. The interaction itself involves the mannose binding lectin FimH at the tip of E. coli pili, which binds oligo-alpha-mannosides on the cell surface glycoprotein uroplakin 1a. The majority of anti-adhesins targeting this interaction have been various alpha-linked mannose glycosides that vary the aglycone moiety. A construct of FimH that contains only the N-terminal ligand binding domain (FimHLD) but not the C-terminal pilin binding domain has been used in the majority of ligand development studies. Recent results, though, show that full-length FimH (FimHFL), is the more therapeutically relevant target. Additionally, we have found that the flexibility of seven membered-ring septanose glycomimetics enable binding to FimH LD. The central hypothesis to be evaluated in the project is that ligands of FimH containing a flexible septanose glycomimetic moiety will be more likely than pyranose-based ligands to effectively bind FimHFL. The proposed project leverages expertise in septanose synthesis (Peczuh) with biochemical and medchem experience, particularly with regard to FimH anti-adhesin development (Ernst), to address the central hypothesis. New septanose FimHFL ligands, whose design is based on previous studies of septanose? lectin binding studies (including FimHLD studies), will be synthesized and evaluated for affinity and bound half-life values. They will also be characterized for selectivity for the target ligand and physicochemical properties. The primary outcome of this project is expected to be a candidate compound with in vitro affinities and physicochemical properties that make it a viable candidate for E. coli infection model studies.
E. coli are the causative organism in millions of urinary tract infections (UTIs) annually. UTIs are a serious health concern that affects women and the elderly at higher rates than the overall population. One potential therapeutic or preventative strategy is to block E. coli from attaching to the lining of urinary tract through the introduction of soluble antagonists of this cell-cell interaction. In this proposal, a potentially new class of antagonists will be synthesized and then evaluated for binding to the protein from E.coli responsible for adhering to cells in the urinary tract. Further, we will also characterize the selectivity and drug-like properties of new compounds.
