Samuel Owen Nitschke

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.

Cell-penetrating bismuth peptides are visualised inside cells by combined X-ray fluorescence (XFM) and optical microscopy. This multimodal approach enables direct tracking of metal-based peptides, offering new insight into bioinorganic therapeutics.

A small series of cationic coumarin amphiphiles, designed to mimic antimicrobial peptides, eradicate MRSA biofilms and show promise as potential antibiofilm agents.

The Buchwald-Hartwig cross-coupling reaction between 4-methylumbelliferone derived nonaflates and amides, carbamates and sulfonamides is described. A wide variety of N-substituted 7-amino coumarin analogues were prepared in good to excellent yields. The photophysical properties of aqueous soluble derivatives were determined and displayed auxochrome based variations. Gram scale synthesis provided an acrylamide analogue which was used to fabricate a fluorescent poly(2-hydroxylethyl methacrylate) (pHEMA) hydrogel that was resistant to leaching in ultrapure H₂O. We envisage our reported protocol to access 4-methylumbelliferone derivatives will find use towards the development of new fluorescent coumarin-based probes by researchers in the field.