# Development of validated probes for the bacterial type III secretion system

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2022 · $743,821

## Abstract

With increasing incidence of antibiotic resistance, development of new therapies against bacterial pathogens is
essential for global public health. The bacterial type III secretion system (T3SS) represents an excellent drug
target because it is externally accessible to small molecules and enables virulence of Pseudomonas,
Salmonella, Chlamydia, and numerous other important pathogens. We have developed a high throughput
screening pipeline to discover T3SS inhibitors and have shown the robustness of our approach through pilot
screens identifying three classes of compounds active against the T3SS. We now propose to broaden our
scope and screen three unique libraries comprising ~58,000 natural product fractions developed by members
of our consortium as well as two commercial synthetic chemical libraries. According to the CDC, every year
over 50,000 healthcare-associated Pseudomonas aeruginosa infections occur in the U.S., >6,000 of which are
caused by multidrug resistant strains. To identify Pseudomonas T3SS inhibitors and potential future
therapeutics, we will carry out the following aims. In Aim 1, we will implement our primary screen and
counterscreens to identify natural product fractions and synthetic compounds with specific T3SS inhibitory
activity. In Aim 2, we will validate hits identified in Aim 1, using three orthogonal distinct approaches. The
identity and structure of bioactive natural products will be determined and initial structure activity analysis
performed on identified synthetic scaffolds. Prioritized compounds will be purified or synthesized and evaluated
for off target activity, if any, as well as breadth of activity against T3SSs in multiple relevant pathogens. In Aim
3, mode of action will be determined, using parallel genetic and biochemical approaches. This rigorous
strategy will provide ~10 T3SS inhibitor chemical probes with identified molecular targets active against P.
aeruginosa and potentially other pathogens.

## Key facts

- **NIH application ID:** 10405053
- **Project number:** 5R01AI141511-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Victoria Auerbuch Stone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $743,821
- **Award type:** 5
- **Project period:** 2019-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405053

## Citation

> US National Institutes of Health, RePORTER application 10405053, Development of validated probes for the bacterial type III secretion system (5R01AI141511-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405053. Licensed CC0.

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