# Development of Gene-Silencing Therapeutics for Pseudomonas aeruginosa

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $1,128,851

## Abstract

PROJECT SUMMARY/ABSTRACT
Gram-negative pathogens are becoming increasingly resistant to many antimicrobials. Furthermore, the pipeline
for new antibiotics is small and new therapies are urgently needed. This can be especially problematic in patients
who suffer from chronic infections or are immunocompromised. Multidrug-resistant Pseudomonas aeruginosa
has been identified by the Centers for Disease Control and Prevention as a serious threat. P. aeruginosa causes
healthcare associated infections in a variety of clinical settings and hosts, but is particularly devastating in
patients with cystic fibrosis (CF). We have been interested in using antisense molecules called PPMOs as
potential therapeutics in these infections. These molecules block messenger RNA and prevent the formation of
the target protein. We have demonstrated that PPMOs can be used to target genes that are essential for
Pseudomonas to grow, such as acpP, lpxC or rpsJ. We showed that blocking these proteins are essential for
Pseudomonas to grow in vitro. We also showed that these PPMOs improve survival in mice that were infected
with Pseudomonas. For this project, we propose to further characterize our lead PPMOs in a larger collection of
Pseudomonas isolates, both antibiotic-sensitive and multidrug-resistant. In addition, efficacy studies will be
performed in both models of pneumonia and bloodstream infection. This process will result in 2-4 PPMOs that
will undergo further pre-clinical testing including toxicity, resistance, pharmacodynamic and pharmacokinetic
studies. By the end of the proposed project, a lead PPMO will have undergone the needed pre-clinical testing
for IND submission to the FDA. This innovative approach to developing novel antibiotics, particularly for P.
aeruginosa, could help expand the increasingly shrinking classes of effective antibiotics that are used to treat
these severe, life-threatening infections.

## Key facts

- **NIH application ID:** 9985745
- **Project number:** 5R01AI141101-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** David Elihu Greenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,128,851
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985745

## Citation

> US National Institutes of Health, RePORTER application 9985745, Development of Gene-Silencing Therapeutics for Pseudomonas aeruginosa (5R01AI141101-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985745. Licensed CC0.

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