# Structural and functional basis of bacterial transcriptional regulation

> **NIH NIH R35** · WESLEYAN UNIVERSITY · 2024 · $399,000

## Abstract

Project Summary / Abstract
 Antibiotic resistance poses an increasingly prevalent public health challenge, but advances in the
development of new drugs has not progressed commensurately. A significant impediment lies in that many
fundamental biochemical processes in bacteria remain poorly understood. The primary goal of the proposed
research is to illuminate how bacteria respond and adapt to changes within their environments from a structural
and mechanistic standpoint. Using the genetically tractable Gram positive organism Bacillus subtilis as our model
system, we will focus our efforts on elucidating the molecular basis for copper-dependent transcriptional
regulation and uncovering the drivers of enzyme specificity during the environmental stress response. Copper is
required for bacterial survival, but excess levels of this transition metal can be toxic. Therefore, copper levels
must be carefully controlled. The mechanisms by which copper export occurs have been extensively studied,
but relatively little is known about copper import. We hypothesize that Cu uptake is regulated by Cu-dependent
transcriptional repressors and the proteins under their control. Here, we will focus on a suite of proteins implicated
in these processes, studying them at a detailed structural, molecular, and cellular level to better understand how
they regulate copper uptake. In parallel, we will investigate what causes a family of very closely related kinases
to specifically regulate distinct functions. Many bacterial species, including Bacillus subtilis and a number of
pathogenic strains, encode one or more kinases that contain a domain termed the Bergerat fold. Despite their
structural commonalities, enzymes with this domain exhibit strong preferences for their physiological binding
partners. However, the molecular basis for how such specificity is conferred has yet to be investigated. We
hypothesize that variations within the Bergerat fold influence substrate specificity and kinetics and can be
targeted by small molecule inhibitors. By integrating tools from structural biology, microbiology, biochemistry,
and computational studies, we will be poised to reveal new paradigms in transcriptional control. The completion
of the proposed studies will catalyze our future investigations into elucidating analogous pathways in pathogenic
strains, uncovering novel members of these families in bacterial phylogeny, and designing small molecule
inhibitors.

## Key facts

- **NIH application ID:** 11099460
- **Project number:** 7R35GM150644-02
- **Recipient organization:** WESLEYAN UNIVERSITY
- **Principal Investigator:** Oriana S Fisher
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,000
- **Award type:** 7
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099460

## Citation

> US National Institutes of Health, RePORTER application 11099460, Structural and functional basis of bacterial transcriptional regulation (7R35GM150644-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11099460. Licensed CC0.

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