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

Antibiotic-resistant infections remain a major challenge in cystic fibrosis (CF), where chronic <i>Pseudomonas aeruginosa</i> 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 <i>Vav3</i> 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 (<i>2S,3S</i>)-<b>BOPC1</b>. Functional assays in CF human airway epithelial cells demonstrated that (<i>2S,3S</i>)-<b>BOPC1</b> significantly reduced <i>P. aeruginosa</i> adhesion in a dose-dependent manner without detectable cytotoxic effects. These findings provide the first evidence that targeting HuR can disrupt the HuR-<i>Vav3</i>-Fn axis, reducing bacterial attachment. This host-directed approach represents a promising strategy to prevent chronic infections in CF without promoting antibiotic resistance.