# Natural Product-Inspired Approaches Toward The Development Of Antivirulence And Species-Specific Inhibitors

> **NIH NIH R35** · EMORY UNIVERSITY · 2021 · $491,373

## Abstract

Project Summary
 The proposed research will interrogate natural product scaffolds as starting points for narrow-spectrum and
antivirulence agents. Of specific interest are compounds that target specific bacteria and/or mitigate bacterial
biofilms, which play a role in 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.
 We will interrogate the chemical synthesis of natural product scaffolds identified from nature that possess
species-specific activity, which is ideal for the development of “narrow-spectrum” therapeutics and tool
compounds. Proposed scaffolds are derived from plant material, fungi, and rhizosphere bacteria and have
previously demonstrated biological activity. We propose to leverage diverted total synthesis to construct both the
lead compound and hypothesis-driven analogs for biological evaluation.
 We will also characterize antivirulence compounds that inhibit biofilm formation. Starting with reported natural
products with biofilm inhibitory activity, 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.
 Finally, we 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:** 10163014
- **Project number:** 2R35GM119426-06
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** William M Wuest
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,373
- **Award type:** 2
- **Project period:** 2016-06-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163014

## Citation

> US National Institutes of Health, RePORTER application 10163014, Natural Product-Inspired Approaches Toward The Development Of Antivirulence And Species-Specific Inhibitors (2R35GM119426-06). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10163014. Licensed CC0.

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