Dual-action thioarylamide-based small molecules to target drug-resistant bacteria and chronic inflammation

We report the synthesis and the antibacterial activity of a library of thioarylamide derivatives, which include N-19004, previously developed as Formyl Peptide Receptor 1 antagonist. These compounds were active against a broad spectrum of pathogens, including clinical strains of <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i>. N-19004 and its analog N-19004-S were proficient in biofilm growth inhibition and disruption. In a murine model of chronic <i>Pseudomonas aeruginosa</i> lung infection, N-19004 significantly reduced bacterial burden and inflammation at low doses. As revealed by Electron Paramagnetic Resonance and Scanning Electron Microscopy analyses, the antibacterial effect of N-19004 mainly derives from its interference with the bacterial membrane bilayer. The formation of long filamentous cells was also observed. With its structural simplicity, good <i>in vivo</i> tolerability, and simultaneous antibacterial and anti-inflammatory activity, N-19004 emerges as a promising candidate for treating multi-drug resistant infections, particularly in cystic fibrosis-related lung disease, where chronic inflammation plays an important role.