# The role of cytochrome bd in uropathogenic Escherichia coli pathogenesis

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2020 · $30,260

## Abstract

PROJECT SUMMARY
Biofilms are multicellular bacterial communities implicated in the majority of bacterial infections, and nearly all
chronic bacterial infections. These communities are nearly impossible to eradicate by traditional
chemotherapeutic approaches and represent a major threat to human health. Biofilm bacteria secrete an
extracellular matrix (ECM) that limits the ability for phagocytes, complement, antibiotics, and other external
stressors to interact with biofilm bacteria. Accordingly, biofilms are highly resistant to antibiotics and the
immune system, often necessitating that patients with biofilm-associated infections receive long-term
suppressive antibiotics or undergo surgery to remove infected tissues. In addition to inhibiting penetrance of
antibiotics and immune defenses, the ECM limits diffusion of nutrients such as oxygen, which, in conjunction
with the metabolic activity of resident bacteria, establishes oxygen gradients within biofilms that render the
interior of biofilms hypoxic. Several studies have demonstrated that oxygen gradients play a critical role in the
development of resilient biofilm communities, and that in biofilms oxygen availability is a central regulator of
bacterial metabolism and expression of ECM components. Previous work in uropathogenic Escherichia coli
(UPEC), the primary cause of urinary tract infections, has demonstrated that despite being a facultative
anaerobe, UPEC relies on aerobic respiration during infection and to form biofilm communities. Through my
thesis research, I have shown that UPEC heterogeneously expresses respiratory enzymes, and that these
enzymes are expressed in discrete subpopulations. Despite this heterogeneity of expression, only expression
of cytochrome bd, a high affinity quinol oxidase necessary for aerobic respiration under hypoxic conditions, is
required for UPEC pathogenesis and biofilm formation. Loss of cytochrome bd, but not other quinol oxidases,
disrupts biofilm development, alters ECM production, increases susceptibility to antibiotics, and impairs
virulence in a murine model of infection. This proposal outlines a series of experiments which will define the
role of cytochrome bd in urinary tract infection pathogenesis and the ability for UPEC to form biofilm
communities capable of withstanding antibiotic therapy and immune assault. Completion of this proposal will
identify bottlenecks that restricts colonization by cytochrome bd deficient UPEC, biochemically define the role
of cytochrome bd in the intracellular phase of urinary tract infection, and define mechanisms by which
cytochrome bd promotes the formation of antibiotic tolerant biofilms. These studies will yield fundamental
insights into how adaptation of central metabolic processes allows bacteria to adapt to diverse host niches and
establish resilient biofilm communities, while also investigating cytochrome bd as a potential drug target to aid
in the prevention or eradication of biofilm-associated infection.

## Key facts

- **NIH application ID:** 10065063
- **Project number:** 1F30AI150077-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Connor James Beebout
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,260
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065063

## Citation

> US National Institutes of Health, RePORTER application 10065063, The role of cytochrome bd in uropathogenic Escherichia coli pathogenesis (1F30AI150077-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10065063. Licensed CC0.

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