文摘
Aminoglycosides are clinically relevant antibiotics that participate in a large variety of molecularrecognition processes involving different RNA and protein receptors. The 3-D structures of these policationicoligosaccharides play a key role in RNA binding and therefore determine their biological activity. Herein,we show that the particular NH2/NH3+/OH distribution within the antibiotic scaffold modulates theoligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkageshave a significant influence on the antibiotic structure. A careful NMR/theoretical analysis of different naturalaminoglycosides, their fragments, and synthetic derivatives proves that both hydrogen bonding and charge-charge repulsive interactions are at the origin of this effect. Current strategies to obtain new aminoglycosidederivatives are mainly focused on the optimization of the direct ligand/receptor contacts. Our results stronglysuggest that the particular location of the NH2/NH3+/OH groups within the antibiotics can also modulatetheir RNA binding properties by affecting the conformational preferences and inherent flexibility of thesedrugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.