# Ring Expanded Glycomimetic FimH Antagonists as Lead Compounds for anti-UTI Therapies

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT STORRS · 2020 · $171,345

## Abstract

SUMMARY
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.

## Key facts

- **NIH application ID:** 9821196
- **Project number:** 5R21AI142363-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** MARK W PECZUH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,345
- **Award type:** 5
- **Project period:** 2018-11-13 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821196

## Citation

> US National Institutes of Health, RePORTER application 9821196, Ring Expanded Glycomimetic FimH Antagonists as Lead Compounds for anti-UTI Therapies (5R21AI142363-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9821196. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*