# Development of DksA-targeted Antibiotics for Treatment of Gram-negative Infections

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

## Abstract

Antibiotic resistant infections disproportionately affect veterans and their families. Antibiotic resistant
Gram-negative bacterial infections are associated with high rates of morbidity and mortality around the
globe, including the men and women actively serving in the armed forces, veterans, and patients in VA
hospitals. Options for antibiotic usage are in dangerous decline. Despite this health crisis, only 24 new
antibiotics have been approved since 1987. Most newer antibiotics are modifications or reformulations of
existing drugs. None of the recently approved antibiotics have novel mechanisms of action, severely
limiting mechanistic diversity among available drugs. The transcription factor DksA, an essential
component of the stringent response that regulates the pathogenesis of diverse Gram-negative bacteria,
is highly conserved among Gram-negative pathogens but is absent from humans. Informed by
bioinformatic modeling and structure-activity relationship (SAR), we have generated new chemical entities
(NCE) that bind to DksA and have antimicrobial activity against nontyphoidal Salmonella and several other
Gram-negative pathogens. Our preliminary pharmacokinetic evaluations indicate that one of our DksA
inhibitors is absorbed and distributed in rats, and exhibits excellent antibiotic activity in an acute murine
model of Salmonella infection. The ultimate goal of the proposed investigations is to develop soluble
compounds against the DksA transcriptional regulator that are endowed with potent antimicrobial activity
against Gram-negative pathogens. Specifically, we propose to 1) synthesize new DksA inhibitors with
improved antimicrobial activity, and 2) characterize ADME (absorption, distribution, metabolism and
excretion) properties and therapeutic potential of DksA inhibitors in animals. Synthesis of DksA inhibitors
will contribute to the rational development of novel antibiotics against Gram-negative bacteria that affect
veterans and the general population.

## Key facts

- **NIH application ID:** 10487785
- **Project number:** 1I01BX005733-01A1
- **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:** 1
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487785

## Citation

> US National Institutes of Health, RePORTER application 10487785, Development of DksA-targeted Antibiotics for Treatment of Gram-negative Infections (1I01BX005733-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10487785. Licensed CC0.

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