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 Staphylococcus aureus and Pseudomonas aeruginosa. N-19004 and its analog N-19004-S were proficient in biofilm growth inhibition and disruption. In a murine model of chronic Pseudomonas aeruginosa 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 in vivo 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.