# Structural biology of c-di-AMP signaling in Gram-positive bacteria

> **NIH NIH R35** · UNIVERSITY OF DELAWARE · 2020 · $329,200

## Abstract

Gram-positive bacteria harbor a second messenger signal molecule called
cyclic-di-adenosine monophosphate (c-di-AMP). C-di-AMP levels in bacterial cells
regulate genomic integrity, cell wall homeostasis, biofilm formation, virulence, induction
of host immune responses, and development of resistance to β-lactam antibiotics. The
intracellular concentration of this centrally important second messenger c-di-AMP is very
critical to cellular physiology. However, the mechanisms of the precise regulation of c-di-
AMP levels and c-di-AMP-mediated changes in gene expression are not completely
understood. This is primarily due to the lack of structural information of proteins involved
in these processes. A combination of three-dimensional structure determination with
biochemical and genetic analysis is the best approach to accurately determine the
details of how c-di-AMP levels are regulated and how does c-di-AMP exerts its affect on
the activity of receptor proteins in mediating gene expression regulation. Therefore, we
will use X-ray crystallography techniques coupled with novel in vitro and in vivo activity
assays to determine a comprehensive view of how c-di-AMP metabolism and functions
are accomplished in bacteria. These studies will pave our way for screening and
development of compounds that can enhance or reduce the activity of key proteins
thereby enabling the fine-tuning of c-di-AMP levels in the cell. Some of the many
possible potential applications of such selected compounds include their use (a) as
adjuvants to β-lactam thereby restoring the efficacy of these antibiotics, (b) to facilitate
the development of robust biofilms of commensal microflora, and (c) to develop
commensal bacteria into efficient mucosal delivery systems of c-di-AMP vaccine
adjuvant into host.
 The overall goal of our laboratory is to elucidate mechanistic details of c-di-AMP
regulation and eventually exploit this knowledge to develop non-traditional methods that
will specifically target the pathogenic bacteria while sparing the commensal bacteria and
strengthening the host's immune response.

## Key facts

- **NIH application ID:** 9932441
- **Project number:** 5R35GM119504-06
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Vijay Kumar Parashar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,200
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932441

## Citation

> US National Institutes of Health, RePORTER application 9932441, Structural biology of c-di-AMP signaling in Gram-positive bacteria (5R35GM119504-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932441. Licensed CC0.

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