# Discovery of New Antibacterial Targets: Probes and Inhibitors of Histidine Kinase Proteins

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $303,566

## Abstract

Bacteria rely on signal transduction pathways to respond to environmental cues. Their ability to specifically
and sensitively detect the presence or absence of a single chemical entity amongst the background of
thousands of other molecules is essential for their survival. Two-component systems (TCSs; generally 20-120
discrete systems per organism) are crucial for the translation of this complex molecular environment into
bacterial action, ranging from growth to antibiotic resistance to virulence. Despite the central role of TCSs to an
organism’s adaptive response, technical challenges have hampered their study, limiting our understanding of
how the combined transmission of the signals from many TCSs are coordinated by the cell to orchestrate
survival and pathogenesis.
 A small number of TCSs have been identified as important targets for the development of antibacterial
agents. However, it is clear that the complex process of bacterial signaling holds many additional targets that
will be critical for combating the rapidly approaching “post-antibiotic era.” The goal of the proposed research is
to develop and apply the tools and techniques required to study the regulation of the histidine kinases, the key
proteins required for TCS-mediated bacterial signaling. Histidine kinases directly sense external stimuli and
transmit this chemical message inside of the cell, promoting the regulation of gene expression. Ultimately, the
tools and knowledge amassed in this work will enable us to understand and predict how a signal is propagated
into bacterial action and to hijack the TCSs for the treatment of infectious disease. These goals will be
accomplished by pursuit of three Aims. Aim 1. Develop ATP-based molecules as activity-based probes for
assessment of histidine kinase activation. Aim 2. Globally map histidine kinase activation from environmental
stressors, antibiotic exposure, and host interactions to identify the key HKs required for rapid bacterial
adaptation and survival. Aim 3. Utilize multi-histidine kinase inhibitors to determine the proteins that are major
contributors to pathogenicity and virulence phenotypes.
 It is clear that there is a dire need for new approaches to the treatment of antibiotic-resistant infections –
the antibiotic pipeline has focused on the “death phenotype,” which has led to the rapid rise of antibiotic
resistance and a severe lack of molecules that function through novel mechanisms-of-action. Control of
behavioral phenotypes, especially pathogenesis and virulence, is an exceptionally promising but unrealized
approach for the control of infectious disease. Our highly interdisciplinary and innovative approach will enable
us to assemble a critical understanding of TCS-mediated signal transduction, with particular emphasis on
characterization of the HKs required in pathogenesis- and virulence-associated processes.

## Key facts

- **NIH application ID:** 10126874
- **Project number:** 5R01GM134538-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Erin Elizabeth Carlson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $303,566
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126874

## Citation

> US National Institutes of Health, RePORTER application 10126874, Discovery of New Antibacterial Targets: Probes and Inhibitors of Histidine Kinase Proteins (5R01GM134538-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10126874. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*