# Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2023 · $508,711

## Abstract

SUMMARY
The larger goal of the project is to identify infection-dependent weaknesses of Gram-negative bacterial
pathogens that could be exploited chemically. We focus on the human pathogen Salmonella enterica serovar
Typhimurium (S. Typhimurium) and its survival within mammalian cells and use cell culture infection models
and small molecules as tools. We and others have observed that some small molecules that are not effective
against Gram-negative bacteria in media prevent pathogen survival during infection of cells and animals.
Gram-negative bacteria likely become vulnerable during infection to small molecules because a variety of host
innate immune mechanisms permeabilize the bacterial cell envelope and/or occupy efflux pumps, enabling
compounds to reach a periplasmic or cellular target. When laboratory media imitates host innate immunity by
permeabilizing the outer membrane, these compounds inhibit bacterial growth. We have identified small
molecules that under broth conditions that permeabilize the outer membrane or in protoplasts, dissipate
bacterial inner membrane voltage without physically disrupting the lipid bilayer. Membrane voltage disruption
could compromise bacteria by, for instance, interfering with energy production and/or activating stress-
response signaling. The compounds do not disrupt mammalian membranes at concentrations that kill S.
Typhimurium in macrophages and at least one of the compounds reduces tissue colonization in mice,
demonstrating in vivo potential for this approach. The Specific Aims will interrogate five distinct molecule
classes to determine whether targeting the inner membrane should be pursued as a novel approach to fighting
Gram-negative bacterial infections.

## Key facts

- **NIH application ID:** 10592676
- **Project number:** 1R01AI168916-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Corrella S Detweiler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $508,711
- **Award type:** 1
- **Project period:** 2023-08-07 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592676

## Citation

> US National Institutes of Health, RePORTER application 10592676, Infection-Dependent Vulnerabilities of Gram-negative Bacterial Pathogens (1R01AI168916-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10592676. Licensed CC0.

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