# HuR-Targeted Small Molecules Reduce Pseudomonas aeruginosa Adhesion in Cystic Fibrosis Airway Epithelial Cells

## TL;DR

This study shows that a new small molecule can reduce Pseudomonas aeruginosa adhesion in cystic fibrosis airway cells by targeting the HuR protein.

## Contribution

The paper introduces (2S,3S)-BOPC1, a HuR-targeted molecule that disrupts bacterial adhesion in CF cells without cytotoxicity.

## Key findings

- (2S,3S)-BOPC1 significantly reduced Pseudomonas aeruginosa adhesion in CF airway cells.
- The molecule disrupted the HuR–Vav3–Fn axis without causing cytotoxic effects.
- This host-directed approach may prevent chronic infections without promoting antibiotic resistance.

## Abstract

Antibiotic-resistant infections remain a major challenge in cystic fibrosis (CF), where chronic Pseudomonas aeruginosa colonization drives lung infection. The overexpression of adhesion-related proteins and extracellular matrix components, including fibronectin (Fn), facilitates bacterial colonization. Recent evidence identifies the RNA-binding protein Human Antigen R (HuR) as a key regulator of this process, as it stabilizes Vav3 mRNA, promoting Fn deposition and the formation of bacterial docking platforms. Here, we report the synthesis, optimization, and functional evaluation of the HuR-targeted small-molecule (2S,3S)-BOPC1. Functional assays in CF human airway epithelial cells demonstrated that (2S,3S)-BOPC1 significantly reduced P. aeruginosa adhesion in a dose-dependent manner without detectable cytotoxic effects. These findings provide the first evidence that targeting HuR can disrupt the HuR–Vav3–Fn axis, reducing bacterial attachment. This host-directed approach represents a promising strategy to prevent chronic infections in CF without promoting antibiotic resistance.