# Photoelectrocyclizations to Virulence Inhibiting Natural Products

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $305,000

## Abstract

The increasing prevalence of drug resistant bacteria has resulted in a dire need for new approaches 
to antimicrobials. In particular, the discovery and development of small 
molecules that are not as predisposed to selective pressure and, as a consequence, offer 
fewer opportunities for the development of resistance, is a topic of current interest and one where 
we believe we can help to make a difference. This proposal outlines our program is 
concentrated on developing novel scaffolds aimed at disrupting bacterial communication and 
 virulence, especially in gram-positive bacteria. We propose to study two natural product 
lead molecules over the course of four phases that combine the development of organic chemistry 
methodology with total synthesis and SAR. Concurrent to these efforts will be studies whose goals 
are to ascertain the ability of our synthetic compounds to control virulence. The choice of 
inhibitors to begin our studies has taken into account the accessibility of the small molecule 
targets using efficient and novel chemical synthesis methodology, the activity of the targets 
against virulence targets, including sortase A, and the ability of the compounds to 
inhibit biofilm formation and to disrupt preformed biofilms. Our lead structures are 
discorhabdin Z, a pyrroloiminoquinone natural product that comes from the marine sponge, Sceptrella 
sp. and taxodone, a diterpene natural product of the abietane family that comes from the roots of 
the sage Salvia austriaca. Both of these agents will synthesized using a unique and 
stereoselective bis-aryl alkene photochemical electrocyclization reaction sequence. We will 
continue to develop and optimize the photoelectrocyclization reactions over the course of the 
proposed efforts. In the third phase of the program we will generate analogs of 
discorhabdin Z and taxodone aimed at enhancing their virulence activity while tempering, 
for the discorhabdins, their cytotoxicity. The final phase of the work proposed here 
will be carried out in collaboration with the University of Utah Medicinal Chemistry Core 
Facility and will target the development of a panel of assays aimed at gathering information about 
the antibiotic activity, anti-biofilm activity, sortase A activity, and toxicity of all of our 
synthetic compounds.

## Key facts

- **NIH application ID:** 10379449
- **Project number:** 5R01GM132531-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** JON Douglas RAINIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $305,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379449

## Citation

> US National Institutes of Health, RePORTER application 10379449, Photoelectrocyclizations to Virulence Inhibiting Natural Products (5R01GM132531-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10379449. Licensed CC0.

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