# Pathogenic Fiber Formation in Bacteria: Structural Basis

> **NIH NIH R37** · WASHINGTON UNIVERSITY · 2024 · $472,500

## Abstract

PROJECT SUMMARY/ABSTRACT:
With dire predictions of antibiotic resistance reaching a tipping point, it is imperative that novel, antibiotic-sparing
medicines are developed to avoid facing increasing deaths due to previously treatable common infections. This
project is focused on this mission by elucidating potential therapeutic targets critical in host-pathogen interactions
for urinary tract infections (UTI), one of the most common infections leading to significant antibiotic use and
economic burden. Over 11 million women suffer from UTIs in the U.S. per year. Further, 20-30% of women
diagnosed with a UTI will experience a recurrent UTI (rUTI) in the following months, resulting in a serious
deterioration in the quality of life through pain, discomfort, disruption of daily activities, and increased healthcare
cost. This problem is exacerbated by rising antimicrobial resistance among uropathogenic Escherichia coli
(UPEC), the cause of over 80% of uncomplicated UTIs. Rates of antibiotic resistance are confounding UTI
treatment for millions of women annually. One critical aspect of uropathogenesis is the ability of bacteria to bind
to host tissues to establish an infection or colonization. Gram-negative bacteria typically utilize adhesive
chaperone usher pathway (CUP) pili, tipped with adhesins that bind to receptors with stereochemical specificity,
mediating host and tissue tropisms. Pilus adhesins are two-domain molecules consisting of a C-terminal pilin
domain that links the adhesin to the pilus tip and an N-terminal receptor-binding domain. The pangenome of E.
coli alone encodes thirty-eight distinct CUP pilus types and single E. coli genomes encode as many as 16, each
likely mediating colonization of a particular habitat. However, only a handful of UPEC adhesins have been
investigated to date. Each of them play critical roles in particular niches. FimH mediates critical binding to
mannose residues on bladder tissue to promote invasion into superficial facet cells during acute cystitis; FmlH
mediates binding to galactose moieties on inflamed bladder epithelial tissue during chronic cystitis; PapG
mediates binding to human kidney during pyelonephritis; and UclD mediates colonization of the gut where UPEC
forms a reservoir. Catheterization increases the susceptibility of the urinary tract to infection with a wider variety
of strains, including Acinetobacter baumanii resulting in increasingly common multidrug resistant catheter-
associated UTIs (CAUTI). Acinetobacter baumanii are known to encode at least two CUP pili known to be
important in CAUTI. This proposal seeks to elucidate: i) the molecular dynamics of adhesin conformational
equilibriums that govern host-pathogen interactions; ii) structure-function correlates of UPEC CUP adhesins with
unknown functions; and iii) structure-function correlates of Acinetobacter baumanii CUP adhesins critical in
CAUTIs. This proposal will enhance the understanding of the mechanism of action of host-pathogen inte...

## Key facts

- **NIH application ID:** 10761707
- **Project number:** 5R37AI048689-24
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** SCOTT J. HULTGREN
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,500
- **Award type:** 5
- **Project period:** 2001-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10761707

## Citation

> US National Institutes of Health, RePORTER application 10761707, Pathogenic Fiber Formation in Bacteria: Structural Basis (5R37AI048689-24). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10761707. Licensed CC0.

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