Probing the Specificity of Aminoglycoside−Ribosomal RNA Interactions with Designed Synthetic Analogs

Alper, Phil B.; Hendrix, Martin; Sears, and Pamela; Wong, Chi‐Huey

doi:10.1021/ja972599h

Cited by 205 publications

(149 citation statements)

References 59 publications

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“…Binding affinities of modified aminoglycosides correlate with the number and basicity of cationic ammonium groups [61], supporting a general model for the interaction of cationic antibiotics with RNA based on structural electrostatic complementarity [60]. Similar findings were reported from screening of designed neomycin B analogs targeting the A site of eubacterial 16S rRNA [93]. The A site [94] and HIV-1 RRE [101] were used for binding studies of aminoglycoside mimetics obtained by conventional [94] and combinatorial [101] synthetic derivatization of the neamine core with amino acids [101] and various amines [94].…”

Section: Rational Design and Combina-torial Synthesis Of Rna Binderssupporting

confidence: 71%

“…Among these methods, surface plasmon resonance (SPR) has extensively been used to study the binding of aminoglycoside derivatives to HIV-1 RRE [90] and oligonucleotides representing the bacterial 16S rRNA A site [91][92][93][94]. In order to perform SPR experiments, the RNA was biotinylated and immobilized on streptavidin-coated chips [90].…”

Section: Rational Design and Combina-torial Synthesis Of Rna Bindersmentioning

confidence: 99%

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Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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RNA molecules are the only known molecules which possess the double property of being depository of genetic information, like DNA, and of displaying catalytic activities, like protein enzymes. RNA molecules intervene in all steps of gene expression and in many other biological activities. Like proteins, RNAs achieve those biological functions by adopting intricate three-dimensional folds and architectures. Further, as in protein sequences, RNA sequences contain signatures specific for threedimensional motifs which participate in recognition and binding. In regulatory pathways, RNA molecules exist in equilibria between transient structures differentially stabilized by effectors such as proteins or cofactors. Therefore, RNA molecules display their potential as drug targets on different levels, namely in three-dimensional folds, in structural equilibria and in RNA-protein interfaces. Several examples will be described together with the already available techniques for combinatorial synthesis and high-throughput screening of potential drug and target RNA molecules.

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Section: Rational Design and Combina-torial Synthesis Of Rna Binderssupporting

confidence: 71%

Section: Rational Design and Combina-torial Synthesis Of Rna Bindersmentioning

confidence: 99%

Rational Drug Design and High-Throughput Techniques for RNA Targets

Hermann

Westhof²

2000

CCHTS

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“…Wong and coworkers (1,17) suggested that the 1,3-hydroxylamine moiety present in almost all aminoglycoside antibiotics may be an important recognition motif for RNA binding. They investigated small molecules that recognize RNA with the 1,3-hydroxylamine motif as a core (1,17).…”

Section: Resistance To Aminoglycosides and Strategies To Counter Itmentioning

confidence: 99%

Aminoglycosides: Perspectives on Mechanisms of Action and Resistance and Strategies to Counter Resistance

Kotra

Haddad

Mobashery

2000

Antimicrob Agents Chemother

449

314

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“…CR-Neo exhibits reduced bactericidal potency and affinity for the 16S rRNA A site relative to Neo (3,8,9,48). However, differential affinity for the A site is not the likely basis for the differential antibacterial activities of the two drugs, since these two parameters are poorly correlated (1,21,25,44). Our results indicate that the enhanced bactericidal potency of Neo relative to that of CRNeo reflects a correspondingly enhanced antitranslational activity, which, in turn, correlates with an enhanced drug-induced restriction of 1492 and 1493 base mobilities.…”

mentioning

confidence: 99%

Defining the Molecular Forces That Determine the Impact of Neomycin on Bacterial Protein Synthesis: Importance of the 2′-Amino Functionality

Barbieri¹,

Kaul²,

Bozza-Hingos³

et al. 2007

Antimicrob Agents Chemother

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2-Deoxystreptamine (2-DOS) aminoglycosides exert their antibiotic actions by binding to the A site of the 16S rRNA and interfering with bacterial protein synthesis. However, the molecular forces that govern the antitranslational activities of aminoglycosides are poorly understood. Here, we describe studies aimed at elucidating these molecular forces. In this connection, we compare the bactericidal, antitranslational, and rRNA binding properties of the 4,5-disubstituted 2-DOS aminoglycoside neomycin (Neo) and a conformationally restricted analog of Neo (CR-Neo) in which the 2-nitrogen atom is covalently conjugated to the 5؆-carbon atom. The bactericidal potency of Neo exceeds that of CR-Neo, with this enhanced antibacterial activity reflecting a correspondingly enhanced antitranslational potency. Time-resolved fluorescence anisotropy studies suggest that the enhanced antitranslational potency of Neo relative to that of CR-Neo is due to a greater extent of drug-induced reduction in the mobilities of the nucleotides at positions 1492 and 1493 of the rRNA A site. Buffer-and salt-dependent binding studies, coupled with high-resolution structural information, point to electrostatic contacts between the 2-amino functionality of Neo and the host rRNA as being an important modulator of 1492 and 1493 base mobilities and therefore antitranslational activities.The increasing prevalence of multidrug-resistant bacterial infections has made the development of new antibiotics an important focus of current pharmacological research. A thorough understanding of the molecular mechanisms that underlie antibiotic action is an essential component of drug development. The 2-deoxystreptamine (2-DOS) aminoglycosides are potent bactericidal agents that target the 16S rRNA A site in the 30S ribosomal subunit, thereby interfering with bacterial protein synthesis (11,12,14,31,45).Recent structural (11, 16-18, 33, 39, 41-43, 47) and biochemical (23, 46) studies have resulted in the proposal of a model for how aminoglycosides exert their deleterious effects on bacterial translation. This model is based on the premise that two conserved adenine residues at positions 1492 and 1493 of the rRNA A site play critical roles in the translation process. According to the model, A1492 and A1493 are in conformational equilibria between intrahelical and extrahelical states. When in their extrahelical states, A1492 and A1493 interact with the codon-anticodon minihelix. This interaction is favored in the presence of a cognate tRNA anticodon and disfavored in the presence of a noncognate tRNA anticodon. The binding of a 2-DOS aminoglycoside shifts the conformational equilibria of A1492 and A1493 toward the extrahelical state, thereby resulting in an enhanced interaction with the codon-anticodon minihelix, even when the tRNA anticodon is noncognate. The net results of this drug-induced effect are mistranslation, premature termination of translation, and inhibition of translation initiation (12). Consistent with this model for the antitranslational impact of am...

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Probing the Specificity of Aminoglycoside−Ribosomal RNA Interactions with Designed Synthetic Analogs

Cited by 205 publications

References 59 publications

Rational Drug Design and High-Throughput Techniques for RNA Targets

Rational Drug Design and High-Throughput Techniques for RNA Targets

Aminoglycosides: Perspectives on Mechanisms of Action and Resistance and Strategies to Counter Resistance

Defining the Molecular Forces That Determine the Impact of Neomycin on Bacterial Protein Synthesis: Importance of the 2′-Amino Functionality

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