# A novel pathway altering OM permeability

> **NIH NIH R03** · TEXAS A&M UNIVERSITY · 2024 · $71,874

## Abstract

PROJECT SUMMARY
The gram-negative outer membrane (OM) represents a strong permeability barrier that impedes the entry of
many antibiotics. The majority of the species the US Centers for Disease Control and Prevention list as of
“urgent” or “serious” concern for antibiotic resistance are gram-negative in part due to the impermeability of the
OM. In recent years, it has become clear that the permeability of the OM can be altered by the physiological
state of the cell. Specifically, clinically relevant stresses such as nutrient limitation can result in strengthening of
the OM permeability barrier, further decreasing the entry of antibiotics. Elucidation of the pathways responsible
for this strengthening will lead to new targets for the development of small molecules that can weaken the OM
permeability barrier. The laboratory’s long-term goal is to understand the mechanisms that change the
permeability of the OM during periods of clinically relevant stress.
Specifically, this project aims to elucidate a novel link between loss of DNA mismatch repair (MMR) and
alteration of OM permeability in Escherichia coli K12. MMR is a highly conserved DNA repair mechanism found
throughout all domains of life. MMR mutants have been found in clinical antibiotic resistant strains and have
been proposed to be an antecedent to the development of resistance mutations facilitated by an increased
mutation rate. However, preliminary data demonstrate a second pathway where loss of MMR leads to resistance
to a broad range of antibiotics through alteration of OM permeability. Thus, loss of MMR in a host environment
would allow bacteria to survive antibiotics treatment longer, while also increasing the probability that a specific
resistance mutation can develop due to the increased mutation rate. The SOS DNA damage stress response
pathway is not necessary for strengthening the OM permeability barrier demonstrating that a novel pathway
connects loss of MMR to OM permeability.
The central hypothesis of this work is loss of MMR activates a novel pathway involving signal transduction and
transcriptional changes that alter the permeability profile of the OM. This project will elucidate genes involved in
this pathway by identifying transcriptional changes that result from pathway activation leading to altered OM
permeability (Aim 1) and determining the genes that are necessary for the pathway to altered OM permeability
(Aim 2). Completion of the aims will transform understanding of the link between DNA repair and OM
permeability and has the potential to uncover new targets for drug discovery.

## Key facts

- **NIH application ID:** 10838552
- **Project number:** 5R03AI177677-02
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Angela Marie Mitchell
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $71,874
- **Award type:** 5
- **Project period:** 2023-05-08 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838552

## Citation

> US National Institutes of Health, RePORTER application 10838552, A novel pathway altering OM permeability (5R03AI177677-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10838552. Licensed CC0.

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