Discovery of novel coumarin amphiphiles: dual-action antimicrobials with bacteria-mediated biofilm disruption and host-directed immunomodulation

Abstract

Bacterial infections pose a threat to the health of animals and humans, and biofilm formation exacerbates the microbial threat. New antimicrobial agents to address this challenge are much needed. In this study, some new amphipathic compounds derived from the natural product coumarin were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Compound 15 exhibited strong inhibitory effects against Staphylococcus aureus ATCC29213 and four clinical isolates, with a minimum inhibitory concentration (MIC) values ranging from 1 to 4 μg/mL. It also demonstrated rapid bactericidal activity and a low propensity for resistance development. The in vivo activity of compound 15 was supported by good antibacterial and anti-inflammatory effects in a mouse wound infection model. More importantly, the good immunomodulatory effects, the biofilm formation inhibition and biofilm clearance were detectable in the treatment of compound 15, which made it a potential candidate antibacterial for controlling S. aureus forming biofilm infections.