# Project 2: Impact of Antibiotics on Growth Cycle and Toxin Production in S. aureus

> **NIH NIH P20** · IDAHO VETERANS RESEARCH / EDUCATION FDN · 2020 · $224,222

## Abstract

Project 2 - SUMMARY
Background: Staphylococcus aureus remains clinically problematic due to continually evolving antimicrobial
resistance. Pathogenesis is attributed to production of potent extracellular toxins, and recent evidence from
our laboratory has demonstrated that beta-lactam antibiotics, such as nafcillin, both increase and prolong toxin
production in methicillin-sensitive and methicillin-resistant S. aureus (MRSA). The current study investigates
detailed molecular mechanisms by which cell-wall active antibiotics alter the S. aureus divisional apparatus
(divisome) and stimulate toxin production. Hypothesis: We hypothesize that a) cell-wall active antibiotics
induce toxin expression via a unique and uncharacterized pathway, orchestrated directly or indirectly by effects
on the bacterial cell wall divisome; b) antibiotic-induced toxin expression involves divisome elements PBP1
and/or PknB; and c) the conserved extracellular PASTA domain of PBP1 and PknB will serve as a therapeutic
target for S. aureus disease. Specific Aim 1: To determine the transcriptional profile of a clinically relevant S.
aureus strain during different phases of growth and in the presence of nafcillin. Genome-wide expression
analysis will be used to elucidate the transcriptional response to nafcillin throughout the normal bacterial
growth cycle. Specific Aim 2: To determine the role of three divisome proteins, PBP1, FtsZ and PknB Ser/Thr
kinase in nafcillin-induced toxin expression. S. aureus mutants and recombinant proteins will be used to
evaluate the role of divisome elements in the direct, or indirect, recognition and response to nafcillin. Specific
Aim 3: To test the efficacy of immunization against PASTA domain-containing proteins in prevention of
experimental S. aureus disease. Survival and pathogenesis studies will evaluate protective effects of
immunization with S. aureus PASTA domain-containing antigens. This aim will heavily utilize the proposed
HPIC facility. Impact on Human Health: Understanding molecular mechanisms that drive S. aureus toxin
production in response to cell-wall active antibiotics will identify novel targets for disease intervention.
Contribution to Multi-disciplinary Infectious Diseases Research Program: Dr. Bolz brings significant
expertise in intracellular signaling pathways of the host response, and in diverse experimental models and
technical approaches for studying host/pathogen interactions. Under Dr. Bolz's direction, the proposed studies
will establish the use of high-throughput genomic technologies in the Infectious Diseases laboratory. In
addition, targeting divisome proteins for potential new treatment modalities will expand our approach to
antimicrobial development and vaccine design.

## Key facts

- **NIH application ID:** 9928456
- **Project number:** 5P20GM109007-05
- **Recipient organization:** IDAHO VETERANS RESEARCH / EDUCATION FDN
- **Principal Investigator:** Devin Dean Bolz
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $224,222
- **Award type:** 5
- **Project period:** — → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928456

## Citation

> US National Institutes of Health, RePORTER application 9928456, Project 2: Impact of Antibiotics on Growth Cycle and Toxin Production in S. aureus (5P20GM109007-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928456. Licensed CC0.

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