Anti-staphylococcal potential of montanine-type derivatives from amaryllidaceae alkaloids alone and in combination with antibiotics

AIMS: The rising wave of antimicrobial resistant organisms, together with the lack of novel group of antibacterial agents, represents a major concern in modern medicine. This study aims to investigate the anti-staphylococcal potential of two semi-synthetic derivatives of naturally occurring nitrogen-containing molecules (1 nm and 2 nm). METHODS AND RESULTS: The two semi-synthetic analogues were evaluated against reference bacterial strains and clinical bacterial isolates. Furthermore, the most active compound, 1 nm, was subjected to synergistic activity screening with the commercial antibiotics against MRSA. The toxicity profile of 1 nm was further explored using in vitro (HepG2 and HK-2 cells) and in vivo (Galleria mellonella) models, accompanied by an insight into its in silico physicochemical characteristics and cytotoxicity. Our results suggest that this derivative possesses promising activity against clinically relevant staphylococci, while showing a favourable safety and bioavailability profile. In addition, this compound showed synergistic or additive effects in combination with several clinically important antibiotics. CONCLUSIONS: 1 nm demonstrates promising adjuvant anti-staphylococcal activity, with a favourable safety profile and an additive interaction with the last-resort antibiotic linezolid, supporting its potential to mitigate resistance development within combination strategies.