# Bacillus subtilis stress responses

> **NIH NIH R35** · CORNELL UNIVERSITY · 2022 · $787,557

## Abstract

Project Summary/Abstract
 Bacteria and humans have a complex relationship: our abundant commensal organisms
provide numerous benefits, whereas pathogenic bacteria impose a large burden of morbidity and
mortality. The immune system restricts bacterial growth through nutritional immunity, antimicrobial
peptides, lytic enzymes, and phagocytic cells. Potential pathogens respond to these threats by the
activation of specific adaptive responses, many of which are critical for virulence. We study stress
responses in Bacillus subtilis, a model Gram positive bacterium. One project addresses responses to
the changing availability of the essential nutrient metal ions zinc, iron, and manganese. The immune
system restricts the growth of pathogens by metal sequestration, both in tissues (e.g. by calprotectin)
and after phagocytosis. In addition, phagocytic cells kill cells by metal intoxication. We have
demonstrated that metal ion homeostasis relies on specific metal-sensing transcription factors that
respond to limitation and excess of iron (Fur and PerR), manganese (MntR), and zinc (Zur and CzrA).
We will characterize the genes regulated by these transcription factors, their roles in metal
homeostasis, and identify the physiological effects that result from both metal ion limitation and
intoxication. This work will build upon our recent identification of the major efflux systems for both iron
and manganese. The insights from these studies will be directly relevant to the similar stress
responses present in human pathogens. The immune system also restricts the growth of pathogens
by production of antibacterial peptides and lytic enzymes, both of which affect the integrity of the cell
envelope. The cell envelope is also a target for many of our most important antibiotics. In a second
project, we have defined several distinct cell envelope stress responses in B. subtilis, with a focus on
those regulated by alternative sigma factors. We have identified an array of mutants with alterations in
stress response pathways and in key central metabolic pathways that have elevated sensitivity to cell
wall antibiotics, including the critically important beta-lactams. In addition, we explore newly
discovered antibiotic synergies with possible implications for clinical approaches. Selection of
antibiotic resistant suppressors provides a powerful approach for delineating the basis of antibiotic
synergies, and the roles of specific stress response pathways. These pathways are central to cell
envelope homeostasis generally, in addition to their role in sensing and responding to antibiotic-
induced stress, and are implicated in the emergence of antibiotic tolerance and resistance in
pathogens.

## Key facts

- **NIH application ID:** 10329263
- **Project number:** 2R35GM122461-06
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** John D Helmann
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $787,557
- **Award type:** 2
- **Project period:** 2017-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329263

## Citation

> US National Institutes of Health, RePORTER application 10329263, Bacillus subtilis stress responses (2R35GM122461-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10329263. Licensed CC0.

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