# Targeting Bacterial Signaling Cascades as a Novel Antibiotic Strategy

> **NIH VA IK2** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

Background and Veteran significance: Pathogens such as mycobacteria and Staphylococcus aureus, are
not only intrinsically antibiotic resistant, but are rapidly acquiring multi-drug resistant traits. Two billion people
are currently infected with Mycobacterium tuberculosis, and an increasing proportion are resistant to clinical
treatments. Methicillin resistant Staphylococcus aureus (MRSA) is a massive burden in healthcare, and
vancomycin resistant strains are increasingly problematic. These resistant infections are endemic to
developing countries and areas with a regular military presence, causing an increased burden for the Veterans
Administration healthcare system. Furthermore, MRSA infections are a major concern in VA hospitals and
are a significant cost in time, resources, and lives. New effective antibiotics are needed, and development
against novel targets is needed to treat infections caused by these resistant organisms.
Novel antibiotic targets: Protein kinases and phosphatases are critical in transducing cellular and
environmental signals to trigger growth and division or to respond to stress and environmental changes.
Human phosphorylation signaling is well studied, but bacterial signaling is less known and no antibiotics
targeting these pathways exist. Penicillin-binding And Serine/Threonine Associated (PASTA) kinases are
unique transmembrane kinases present in Actinobacteria and Firmicutes. PASTA kinases are necessary for
virulence, making them attractive drug targets. Genetic knockouts in MRSA and pharmacological inhibition in
MRSA or tuberculosis increase β-lactam susceptibility. Furthermore, genetic deletion of the cognate S/T
phosphatase in MRSA increases this synergy and decreases in vivo virulence. Inhibiting both kinases and
phosphatases to enhance β-lactam synergy is a novel approach to antibiotic development.
Goals of this award: The goals of this award are to 1) provide time and resources to facilitate Dr.
Wlodarchak’s transition from a mentored scientist to an independent translational investigator in the VA
system and to 2) develop lead compounds against novel antibiotic targets in MRSA and tuberculosis. The
central hypothesis tested here is that a coordinated attack on several nodes of the serine/threonine
phosphorylation signaling cascade will be an effective pharmacological strategy with low likelihood
of resistance development. This hypothesis will be tested by characterizing hits from a biochemical
phosphatase screen, developing MRSA kinase inhibitors, and performing the first global transcriptomic and
phosphoproteomic screen on MRSA under pharmacologic stress on this pathway.
Expected outcomes and impacts: Upon completion of this award, it is expected that Dr. Wlodarchak will
transition to a fully independent VA investigator with several well-characterized lead compounds against
MRSA and tuberculosis and leads on other potential targets in this pathway. This research will provide
preliminary data for a competitive VA...

## Key facts

- **NIH application ID:** 10509391
- **Project number:** 5IK2BX005082-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Nathan J Wlodarchak
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10509391

## Citation

> US National Institutes of Health, RePORTER application 10509391, Targeting Bacterial Signaling Cascades as a Novel Antibiotic Strategy (5IK2BX005082-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10509391. Licensed CC0.

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