# Chemical Strategies to Map Bacterial Response to Environmental Change

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2024 · $546,107

## Abstract

The Carlson Group applies the diverse tools of chemical biology to understand how bacteria harness their
limited genome to inhabit nearly every ecological niche on our planet. These “simple” single-celled organisms
are remarkable in their ability to respond to and survive in the presence of diverse environmental stressors. This
is largely accomplished through related but specialized proteins that are activated under disparate conditions.
With NIH support, the PI has been investigating two protein families that are crucial to a bacteria’s ability to
respond to its environment and maintain cell wall integrity, histidine kinases (HKs) and penicillin-binding proteins
(PBPs). The PBPs are required for cell wall construction and are the targets of b-lactams, the most used class
of antibiotics in the world. The HKs sense changes in the periplasmic space and transmit this information inside
of the cell, allowing bacteria to respond to fluctuating environments. The HKs are also important in infection and
antibiotic resistance. Clearly, a deeper understanding of when, where, and how the PBPs and HKs are
functionally differentiated and used to enable cell survival will be crucial in combating the rapidly approaching
“post-antibiotic era.” Chemical probes are an essential tool for the characterization of these differentiating factors.
 We have pioneered the development of activity-based probes (ABPs) for the PBP and HK families that
specifically label catalytically active enzymes, yielding a read-out of their functional state. These molecules are
required to investigate how functionally related proteins differ from one another in their catalytic activation,
substrate or ligand recognition, localization, and biomolecular interactions. The overall vision for this MIRA
project is to build on the PI’s foundation of results and leadership in this area and apply a chemical approach to
expand the understanding of these two enzyme families. We will achieve this vision by expanding our library of
PBP-selective ABPs and applying these chemical probes to investigation of the roles of these proteins in cell
growth and division, as well as adaptation to environmental perturbations. We will also optimize the chemical
probes and internalization agents needed to deliver ABPs into the bacterial cytoplasm, enabling global mapping
of HK activation upon exposure to stimuli. Finally, we will validate the HKs as viable targets for the development
of anti-virulence agents and adjuvants and optimize the potency of our lead compounds.
 Our combined expertise in chemical synthesis, ABPs, mass spectrometry-based -omics, biochemistry, and
microbiology make us uniquely qualified to untangle the web of apparent functional redundancy within these
enzyme families. We also have long-standing collaborators with expertise in the HKs and PBPs, as well as
methods critical to this project. The overall impact of this work will be a drastically increased and rigorously tested
understanding of cell...

## Key facts

- **NIH application ID:** 10841774
- **Project number:** 1R35GM153306-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Erin Elizabeth Carlson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,107
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841774

## Citation

> US National Institutes of Health, RePORTER application 10841774, Chemical Strategies to Map Bacterial Response to Environmental Change (1R35GM153306-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841774. Licensed CC0.

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