# Phenylacetic acid catabolism, a novel stress-response pathway in Acinetobacter baumannii

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $681,308

## Abstract

PROJECT SUMMARY/ABSTRACT
Multidrug resistant (MDR) infections caused by the bacterial pathogen Acinetobacter baumannii are increasing
at alarming rates. Currently, over 60 % of global A. baumannii clinical isolates are MDR, leading the Centers for
Disease Control and Prevention and the World Health Organization to categorize it as a top priority for the
research and development of new antimicrobial therapies. In addition to accumulating resistance mechanisms,
A. baumannii strains develop tolerance to antibiotics, which can frequently lead to poor therapeutic outcomes
even with antibiotic susceptible strains. However, the mechanisms used by A. baumannii to adapt to and tolerate
hostile conditions remain largely unknown. We found that A. baumannii employs a novel stress response
pathway in which phenylacetic acid (PAA), a metabolite derived from phenylalanine catabolism, acts as a
signaling molecule. We established that, in the presence of sub-inhibitory concentrations of different antibiotics,
such as trimethoprim/sulfamethoxazole, A. baumannii dramatically increases the transcription of the paa operon
which encodes enzymes required to degrade PAA. Conversely, other conditions, like hydrogen peroxide
treatment, lead to a repression of the paa operon. The regulation of the paa operon triggers a physiological
adaptive response that includes the modulation of pili biosynthesis and biofilm formation. Importantly, we found
that artificial augmentation of PAA levels, through the addition of commercially available PAA-derivatives or
mutations in PAA degradative genes, disrupts this response Furthermore, mutating initial steps of PAA
degradation leads to increased sensitivity to antibiotics and oxidative stress in multiple strains. Here we propose
to use our expertise in A. baumannii genetics and pathogenesis to investigate the PAA-mediated stress response
in Acinetobacter and determine its importance in virulence. We will determine the breadth of PAA signaling using
reporter assays, and we will explore PAA-mediated changes in cell physiology by profiling gene expression
under different stress conditions. Further, we will characterize the PAA-dependent mechanisms of cell signaling
under stress by measuring cellular levels of PAA and determining the role of important regulatory proteins in this
cascade. Finally, we will test the virulence of strains unable to regulate PAA levels in the catheter-associated
urinary tract infection and lung infection murine models. Our work will establish the role of PAA as a key
regulatory molecule in A. baumannii, determine the biological processes regulated by PAA, and uncover the
mechanisms by which PAA triggers adaptations to promote survival under stress. Understanding the
fundamental aspects of the PAA stress response will provide a foundation to future clinical studies.

## Key facts

- **NIH application ID:** 10827427
- **Project number:** 5R01AI166359-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Mario Feldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,308
- **Award type:** 5
- **Project period:** 2022-05-12 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827427

## Citation

> US National Institutes of Health, RePORTER application 10827427, Phenylacetic acid catabolism, a novel stress-response pathway in Acinetobacter baumannii (5R01AI166359-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10827427. Licensed CC0.

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