Abstract
RNA recognition by natural aminoglycoside antibiotics depends on the 2-deoxystreptamine (2-DOS) scaffold which participates in specific hydrogen bonds with the ribosomal decoding-site target. Three-dimensional structure information has been used for the design of azepane-monoglycosides, building blocks for novel antibiotics in which 2-DOS is replaced by a heterocyclic scaffold. Azepane-glycosides showed target binding and translation inhibition in the low micromolar range and inhibited growth of Staphylococcus aureus, including aminoglycoside-resistant strains.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aminoglycosides / adverse effects
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Aminoglycosides / chemistry
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism*
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Anti-Bacterial Agents / pharmacology*
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Azepines / chemistry*
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Azepines / metabolism
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Azepines / pharmacology*
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Drug Design
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Glycosides / chemistry
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Glycosides / metabolism
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Glycosides / pharmacology
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / metabolism
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Heterocyclic Compounds / pharmacology
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Nucleic Acid Conformation
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Paromomycin
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Protein Biosynthesis / drug effects
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RNA, Bacterial / antagonists & inhibitors
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RNA, Ribosomal / antagonists & inhibitors*
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RNA, Ribosomal / chemistry
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / growth & development*
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Structure-Activity Relationship
Substances
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Aminoglycosides
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Anti-Bacterial Agents
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Azepines
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Glycosides
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Heterocyclic Compounds
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RNA, Bacterial
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RNA, Ribosomal
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Paromomycin