# Natural Product-Inspired Approaches Toward the Development of Antivirulence and Species-Specific Inhibitors

> **NIH NIH R35** · EMORY UNIVERSITY · 2020 · $380,777

## Abstract

Project Summary
 The proposed research will interrogate natural product scaffolds as starting points for antivirulence
and narrow-spectrum agents. Of specific interest are compounds that mitigate bacterial biofilms, which
are the causative agent in hospital-acquired infections, the development of resistance in bacteria, the
rejection of medical implants, and many other health related diseases. The compounds, which this
proposal will focus on, have been chosen from privileged areas where bacteria utilize chemical warfare
to prevent colonization of invading species. Here we present a multi-faceted approach, including
organic synthesis, molecular genetics, proteomics, transcriptomics, and microbiological assays that
begins with these privileged scaffolds but has as an overarching goal of developing next generation
therapeutics and tool compounds to better understand processes within a multispecies environment.
 The first two research thrusts seek to identify antivirulence compounds that inhibit one of the
following processes: biofilm formation, quorum sensing, production of virulence factors, etc. Starting
with known antifoulant and signaling molecules, we will explore the unique chemical features that
endow each molecule with their biological effect. Furthermore, we will utilize the chemical toolbox to
design compounds with improved chemical and physical properties to improve the likelihood of
translation. Analogs will then be tested with the goal of identifying specific processes that the natural
product affects and allow for a broader evaluation of the target in general biofilm processes.
 The third research thrust involves the chemical synthesis of natural product scaffolds identified in
the rhizosphere. We have recently shown that these compounds possess species-specific activity,
which is ideal for the development of “narrow-spectrum” therapeutics and tool compounds. Proposed
compounds are derived from plant material, endophytic fungi, and rhizosphere bacteria and have
previously demonstrated biological activity. Central to the efficient and concise strategies proposed is
the knowledge gained in our previously described total syntheses which provides key intermediates for
analog development.
 The final thrust will investigate both the biological target and properties of the tool compounds both
in single species and multispecies biofilms. This approach will employ a combination of genetic and
MS-proteomic techniques to develop a candidate list of proteins, from which we will identify the targets
by biochemical studies. Previous research has demonstrated that these sources have provided
compounds with unprecedented biological activity with significant implications to improving human
health. Furthermore, they act on therapeutic targets that were previously unknown providing new
approaches to combat bacteria.

## Key facts

- **NIH application ID:** 9931237
- **Project number:** 5R35GM119426-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** William M Wuest
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,777
- **Award type:** 5
- **Project period:** 2016-06-30 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931237

## Citation

> US National Institutes of Health, RePORTER application 9931237, Natural Product-Inspired Approaches Toward the Development of Antivirulence and Species-Specific Inhibitors (5R35GM119426-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931237. Licensed CC0.

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