The pattern of distribution of amino groups modulates the structure and dynamics of natural aminoglycosides: implications for RNA recognition.
Aminoglycosides are clinically relevant antibiotics that participate in a large variety of molecular recognition processes involving different RNA and protein receptors. The 3-D structures of these policationic oligosaccharides 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 the oligosaccharide conformation and flexibility. In particular, those polar groups flanking the glycosidic linkages have a significant influence on the antibiotic structure. A careful NMR/theoretical analysis of different natural aminoglycosides, 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 aminoglycoside derivatives are mainly focused on the optimization of the direct ligand/receptor contacts. Our results strongly suggest that the particular location of the NH2/NH3(+)/OH groups within the antibiotics can also modulate their RNA binding properties by affecting the conformational preferences and inherent flexibility of these drugs. This fact should also be carefully considered in the design of new antibiotics with improved activity.
Corzana
Francisco
F
Contribution from the Instituto de Química OrgAnica General and Centro de Investigaciones Biológicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Cuesta
Igor
I
Freire
Felix
F
Revuelta
Julia
J
Torrado
Mario
M
Bastida
Agatha
A
Jiménez-Barbero
Jesús
J
Asensio
Juan Luis
JL
D000588:Amines / Q000737:chemistry; D000617:Aminoglycosides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D002236:Carbohydrate Conformation; D015195:Drug Design; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D018583:Pliability; D012313:RNA / Q000737:chemistry*; D055672:Static Electricity
D000588:Amines; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D012313:RNA