According to NMR and molecular dynamics simulations, the conformational behavior of natural aminoglycosidesis characterized by a remarkable flexibility, with different conformations, even non-exo-anomericones, in fast exchange. Very probably, this feature allows the adaptation of these ligands to the spatialand electronic requirements of different receptors. The large diversity of structures adopted by aminoglycosidesin the binding pocket of the different RNA receptors and the distinct enzymes involved in bacterial resistanceare consistent with this view. This conformational diversity can, in certain favorable cases, be exploitedin the design of new antibiotic derivatives not susceptible to enzymatic inactivation, by designing tailor-madeconformationally locked aminoglycosides.