# Using Salmonella Pathogenesis and Cell Biology as a Discovery Tool

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2024 · $195,625

## Abstract

SUMMARY
The inner membrane of pathogenic Gram-negative bacteria contains lipids and proteins that are distinct from
those of mammalian cell membranes. Inner membranes therefore could be attacked by small molecules during
infection, when soluble host innate immunity damages the protective outer membrane barrier, increasing
access to chemicals. Exploration of molecules that a) interrupt pathogenesis in cell culture with minimal host
cell damage, and b) perturb inner membranes under broth conditions that permeabilize the outer membrane
has the potential to reveal whether bacterial virulence can be short-circuited by compounds that disturb inner
membranes but do not inhibit bacterial growth under standard broth conditions. An in-macrophage cell biology-
based method called SAFIRE appears to identify compounds that negatively affect bacterial inner membranes
while sparing host cell membranes. Within this application we propose to study a SAFIRE-identified compound,
D66, which appears to damage bacterial inner membranes without lysing them. Published and unpublished
preliminary data together indicate that D66 accesses bacterial inner membranes when the LPS layer is
damaged or efflux pumps are compromised, conditions consistent with the macrophage phagosome. However,
D66 disrupts inner membrane voltage rapidly and at concentrations that do not destroy the inner membrane
lipid bilayer, indicating that the compound is not causing bacterial lysis but is disturbing the membrane more
subtly. We hypothesize that D66 damages the bacterial cell membrane in a process that triggers stress
response pathways but does not cause rapid physical disruption of the lipid bilayer. We propose cell biological
and animal infection experiments to test this hypothesis.

## Key facts

- **NIH application ID:** 10795916
- **Project number:** 5R21AI171945-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Corrella S Detweiler
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795916

## Citation

> US National Institutes of Health, RePORTER application 10795916, Using Salmonella Pathogenesis and Cell Biology as a Discovery Tool (5R21AI171945-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10795916. Licensed CC0.

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