# Proof of concept experiments for T3SS inhibitors against burn wound infections

> **NIH NIH R41** · MICROBIOTIX, INC · 2024 · $300,000

## Abstract

ABSTRACT
The overall goal of this proposal is to develop a novel therapy for the treatment of burn wound infections caused
by the opportunistic Gram-negative pathogen Pseudomonas aeruginosa (Paer), a leading cause of burn wound
infections.Paer colonizes 14 to 33% of burn wounds within 14 days after hospital admission. Paer infections
are difficult to treat due to intrinsic antibiotic resistance, its propensity to adopt the biofilm mode of growth within
burn wounds, and the prevalence of strains that are resistant to several antibiotics. In fact, Paer strains that are
resistant to all anti-pseudomonal antibiotics except the antibiotic of last resort, colistin, have been identified,
prompting the CDC to designate Paer as a “Serious Threat” pathogen. To address the need for innovative
therapies to treat Paer burn wound infections, we propose to evaluate a novel class of small molecules that
inhibit the type 3 secretion system (T3SS), the major virulence factor utilized by Paer to establish infections and
to disseminate in the host. In previous research, we have discovered and chemically optimized the
phenoxyacetamides (PhAs), a series of potent, small molecule inhibitors of the Paer T3SS. As the result of
extensive chemical optimization of this series, we have identified five distinct compounds that are potent
inhibitors of T3SS activity in vitro, are drug-like, and are efficacious as single agents against Paer in an
immunocompetent murine pneumonia model, decreasing bacterial load in the lungs by >1 log10 CFU, and
significantly decreasing dissemination to the liver by >1 log10 CFU. Our strategy for achieving the overall goal
of this proposal is to obtain proof-of-principle data demonstrating that the in vivo validated PhA T3SS inhibitors
are efficacious against Paer burn wound infections using in vitro and in vivo burn wound infection models.
Compounds that meet the milestones for in vivo efficacy will be developed further as novel therapy for burn
wound infections in a follow-on Phase II proposal. To achieve the goal of this proposal, we will complete the
following specific aims: Aim 1. Prioritize in vivo validated T3SS inhibitors using an in vitro burn wound model
(MBX, years 1 and 2); Aim 2. Evaluate 2 prioritized T3SS inhibitors in the murine thermal injury infection model
(MGH, years 1 and 2).

## Key facts

- **NIH application ID:** 10913729
- **Project number:** 1R41AI183900-01
- **Recipient organization:** MICROBIOTIX, INC
- **Principal Investigator:** TIMOTHY J. OPPERMAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2024-04-12 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913729

## Citation

> US National Institutes of Health, RePORTER application 10913729, Proof of concept experiments for T3SS inhibitors against burn wound infections (1R41AI183900-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10913729. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*