# Targeting the bacterialthioesterase, PqsE, for the treatment of Pseudomonas aeruginosa infections

> **NIH NIH F32** · PRINCETON UNIVERSITY · 2020 · $65,310

## Abstract

PROJECT SUMMARY/ABSTRACT
 Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for a high incidence of life-
threatening hospital-acquired infections. P. aeruginosa pathogenicity relies on the process of bacterial cell-cell
communication known as quorum sensing. Quorum-sensing bacteria produce, release, and, as a coordinated
group, detect the buildup of extracellular signal molecules, called autoinducers. Quorum sensing allows bacteria
to count the members of the vicinal community and undertake collective behaviors only when there are enough
cells present for group behaviors to effectively promote survival and/or infection. P. aeruginosa has two main
quorum-sensing systems, each composed of an autoinducer synthase and an autoinducer receptor (LasI/LasR
and RhlI/RhlR). A new protein, the thioesterase, PqsE, has been identified by the Bassler laboratory to possess
an activity that allows the RhlR arm of the quorum-sensing system to be activated in the absence of the
canonical, RhlI-produced autoinducer. Importantly, deletion of pqsE makes P. aeruginosa completely avirulent
in nematode and mouse models of infection, as does deletion of rhlR. These findings reveal PqsE as an exciting
new target for anti-microbial drug design to combat P. aeruginosa infections. The goals of this research are to
1) develop potent small molecule inhibitors of PqsE and 2) use inhibitor-bound PqsE structures to design point
mutations to dissect the roles PqsE plays in quorum sensing. I will use multiple chemical screening strategies to
discover molecules that inhibit PqsE function, optimize those lead molecules through rounds of synthetic
diversification, and characterize their mechanisms of action. Crystallography of my inhibitors bound to PqsE will
be used to inform the design of genetic tools to investigate how PqsE differentially regulates gene expression
under planktonic and biofilm growth conditions. My work will provide an understanding of how PqsE contributes
to quorum sensing in P. aeruginosa, and with new molecules in hand that interfere with the process, the field
can develop strategies to treat deadly hospital-acquired infections. In order to accomplish the goals of this
project, I will utilize techniques in chemistry, biochemistry, and structural biology, and I will learn techniques in
microbiology and bacterial genetics. With the development of these skills over the course of the next three years,
I aim to gain independence as an interdisciplinary researcher and project leader. This will prepare me for, and
form the basis of running my own research program in an academic lab, beyond my postdoctoral work at
Princeton University.

## Key facts

- **NIH application ID:** 10059135
- **Project number:** 5F32GM134583-02
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Isabelle Taylor
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10059135

## Citation

> US National Institutes of Health, RePORTER application 10059135, Targeting the bacterialthioesterase, PqsE, for the treatment of Pseudomonas aeruginosa infections (5F32GM134583-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10059135. Licensed CC0.

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