Cationic metal-binding coumarin amphiphiles as membrane-active antimicrobial agents

Synthetic mimetics of antimicrobial peptides (AMPs) typically rely on amine or guanidine groups to provide an overall cationic charge, often overlooking the metal-binding functionalities that influence AMP-membrane interactions. Here, we report three coumarin amphiphiles incorporating hydrophilic metal-binding headgroups and demonstrate that this design strategy yields improved potency and selectivity. All three compounds displayed strong antibacterial activity against methicillin-resistant S. aureus (MRSA), and a diethylenetriamine (DETA) derivative was also active against the Gram-negative bacteria, A. baumannii and E. coli. The compounds also showed moderate activity against MRSA biofilms, reducing the biomass of established MRSA biofilms by 40-50%. Mechanistic investigations revealed that the DETA and cyclen derivatives increased the outer-membrane permeability of E. coli and potentiated the activity of minocycline and rifampicin. All three amphiphiles also exhibited potent antifungal activity against C. neoformans, surpassing the activity of the clinical control fluconazole, with the DETA analogue also displaying activity against C. albicans. Collectively, these results suggest that incorporating metal-binding headgroups into amphiphilic scaffolds may engage a distinct mode of action compared to traditional small-molecule AMP mimetics, resulting in increased antimicrobial potency and selectivity over mammalian membranes.