# Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

Infectious diarrhea afflicts a billion people a year and is responsible for 4% of all human deaths. Many of
the 2,500 serovars of nontyphoidal Salmonella enterica are common causes of infectious diarrhea in the
general population, active military servicemen and veterans. As is the case for Salmonella, the number
of bacteria resistant to antibiotics is steadily increasing. Antibiotic resistance in Gram-negative bacilli is
becoming a clinical problem of epic proportions with few therapeutic agents in the horizon. Future
prophylactic and therapeutic approaches against drug resistant bacteria will greatly benefit from a deeper
understanding of the molecular mechanisms of bacterial pathogenesis. The research of our group and
many others has shown critical roles for the RNA polymerase regulatory protein DksA in the
pathogenesis of multiple Gram-negative bacilli, including Salmonella, Shigella, Campylobacter,
Haemophilus, Pseudomonas, and Vibrio. We have discovered that conserved cysteine residues in the
DksA zinc finger are not only important for Salmonella pathogenesis but also represent a novel sensor of
oxidative stress. The proposed research will test the hypothesis that the DksA zinc finger forms a stable
sulfenic acid in response to low levels of oxidative stress, thereby activating transcription. At higher levels
of oxidative stress, however, the oxidoreductase activity of the DnaJ chaperone catalyzes disulfide bond
formation in DksA zinc finger, a redox state that represses gene transcription. This model is highly
innovative because it defines DksA as a thiol multiplex with discrete regulatory outputs according to
degree of oxidation of cysteine residues in the zinc finger. Our investigations will contribute to a deeper
understanding of critical steps in bacterial pathogenesis and will also help the rational development of
antibiotics against phylogenetically diverse Gram-negative bacilli. Based on our basic knowledge of
DksA, we have already identified a drug that targets a pocket at the tip of the coiled-coil domain of this
RNA polymerase regulatory protein. This novel compound has excellent antibiotic activity against
Salmonella and E. coli. The proposed research will help develop and test novel antibiotics against
conserved pockets in DksA. Our investigations will aid with the rational development of future therapies
against a variety of Gram-negative, often antibiotic resistant, bacteria that cause high rates of morbidity
and mortality in veterans and their families.

## Key facts

- **NIH application ID:** 9898263
- **Project number:** 5I01BX002073-08
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Andres Vazquez-Torres
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898263

## Citation

> US National Institutes of Health, RePORTER application 9898263, Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species (5I01BX002073-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898263. Licensed CC0.

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