Lipidated Aminoglycosides as New Tools that Repurpose Old Natural Antibiotics for New-Fangled Utility

Aminoglycosides have long served as indispensable antibacterial agents, yet their clinical utility has diminished due to toxicity and pervasive resistance with the advent of superbugs. Over the past decade, however, a renewed chemical interest transformed these classical antibiotics into versatile molecular scaffolds through various covalent modifications. Among these the lipidation, a strategy that fundamentally reprograms their biological behavior is of particular interest. By installing hydrophobic or amphiphilic domains onto the polycationic 2-deoxystreptamine framework, aminoglycosides acquire a new mode of action that diverges strikingly from ribosomal targeting. Lipidated aminoglycosides emerge as potent membrane-active agents capable of overcoming multidrug resistance, penetrating biofilms, eradicating persister cells, and displaying broad-spectrum antifungal activity. In parallel, their intrinsic RNA affinity and enriched cationic functionality enable efficient condensation with nucleic acids, endosomal escape, and the formation of self-assembled nanostructures. This positions lipidated aminoglycosides as promising candidates for nonviral DNA, siRNA, and mRNA delivery. This review focuses on the chemical logic, methods, and mechanistic insights that underpin the evolution of lipidated aminoglycosides from early acylated derivatives to modern amphiphilic, guanidinium-linked, sterol conjugated, and ionizable aminoglycoside lipids.