# Uncovering aryl polyene biology to identify new drug targets in Gram-negative bacterial pathogens

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $402,500

## Abstract

ABSTRACT
We are rapidly running out of options to combat infectious diseases in an era that is marked by a rise in antibiotic
resistant bacterial pathogens. The discovery rate of novel antibiotics is not keeping up with this pressing need
and thus we have to identify alternative drug targets and develop complementary elimination strategies. This is
a particularly challenging task for infections caused by Gram-negative bacteria because their outer membrane
is impermeable to many compounds. We discovered an aryl polyene (APE) virulence factor, widespread among
Gram-negative pathogens, and here propose to characterize its biosynthesis and use it as a target for the
development of elimination strategies. APEs are the product of the most abundant family of biosynthetic gene
clusters (BGCs) in our global in silico analysis of bacterial genomes. They are present in several multidrug-
resistant pathogens, and our preliminary data shows that APEs are esterified to a yet unidentified anchor
molecule in the Gram-negative outer membrane. Furthermore, we discovered that APEs serve as virulence
factors that protect their producers from host innate immune clearance mechanisms. Our long-term goal is to
understand APE biology on a molecular, functional and evolutionary level.
The current proposal is centered on the hypothesis that APE biosynthesis and cell envelope localization provide
targets for specific antivirulence strategies against Gram-negative pathogens. We will test this by first
characterizing the function of individual genes within the APE outer membrane localization pathway and
identifying the APE-containing anchor molecule. Next, we will determine the environmental conditions that
control regulation of APE expression using a forward genetics approach. Finally, we will develop interference
strategies to inhibit APE production, using a targeted inhibitor of the initiation enzyme in the biosynthetic pathway.
Our proposed project will yield mechanistic insights into the biology of APEs, as well as identify small molecule
tool compounds that can be used to study APE biology and enable alternative pathogen eradication strategies.

## Key facts

- **NIH application ID:** 10800663
- **Project number:** 5R01AI153173-04
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jan Claesen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800663

## Citation

> US National Institutes of Health, RePORTER application 10800663, Uncovering aryl polyene biology to identify new drug targets in Gram-negative bacterial pathogens (5R01AI153173-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10800663. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*