The synthesis of 6′-N-acyl neamine-based amphiphiles: Synergistic activity against Pseudomonas aeruginosa via enhanced membrane permeability

Amphiphilic aminoglycosides offer a promising approach to combat antibiotic resistant Gram-negative bacteria. Here, a series of neamine-based amphiphiles bearing alkyl chains of varying lengths (C4–C16) was synthesized via a concise route through selective modification at the 6′-amino position of neamine. Antibacterial evaluation revealed a chain length–dependent activity, with the C14- and C15-alkyl neamine amphiphiles exhibiting the most potent antibacterial activity against ESKAPE pathogens. The C15 derivative displayed superior activity compared to neamine and synergized with multiple clinical antibiotics against P. aeruginosa. Mechanistic studies indicated that this synergy results from enhanced outer membrane permeability, and cytotoxicity assays confirmed low toxicity at therapeutically relevant concentrations.