# Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

Infectious diarrhea afflicts a billion people a year and is responsible for approximately 4% of all human
deaths worldwide. Salmonella enterica are common causes of infectious diarrhea in humans, and often
plague active military servicemen and veterans. Salmonella are among the most frequent bacterial
isolates resistant to antibiotics. The antibiotic resistance crisis is becoming a clinical problem of epic
proportions, as the number of therapeutic compounds in the pipeline is dwindling. Future prophylactic
and therapeutic approaches against drug resistant bacteria will greatly benefit from the identification of
molecular targets in pathogens. During the last 20 years only 4 novel compounds have been introduced
in the clinic, all of which represent new mechanisms identified through basic understanding of molecular
pathogenesis. As holds true for all human pathogens, precise regulation of RNA polymerase controls
essential aspects of Salmonella pathogenesis, and the expression of antibiotic resistant programs. Our
investigations have shown that allosteric interactions of DksA and Gre factors with RNA polymerase
regulate vital facets of Salmonella pathogenesis and antibiotic resistance. The proposed research will
elucidate the mechanisms by which the DnaK/DnaJ chaperone couple regulates interactions of DksA
with RNA polymerase, thereby engaging fundamental Salmonella virulence programs. We will also
characterize how binding of Gre factors to the secondary channel of RNA polymerase provides a
previously unsuspected level of regulation of Salmonella pathogenesis and antibiotic tolerance.
Specifically, we will test the role that the transcriptional proofreading associated with Gre factors plays in
resistance of Salmonella to the bactericidal activity inherent to the NADPH oxidase. Our investigations
will also characterize how Gre factors modulate the expression of a type III secretion system that is vital
to the intracellular lifestyle of Salmonella, while bolstering resistance to aminoglycoside antibiotics that
poison bacterial translation. Our investigations will aid in the rational development of future therapies
against a variety of Gram-negative, antibiotic resistant bacteria that cause high rates of morbidity and
mortality in active servicemen, veterans and their families.

## Key facts

- **NIH application ID:** 10620159
- **Project number:** 5I01BX002073-11
- **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:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620159

## Citation

> US National Institutes of Health, RePORTER application 10620159, Molecular Analysis of Bacterial Adaptive Response to Host Reactive Species (5I01BX002073-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10620159. Licensed CC0.

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