Abstract
Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminoglycosides / chemistry*
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Aminoglycosides / pharmacology*
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Aminoglycosides / therapeutic use
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Animals
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Base Sequence
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Cell-Free System
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Crystallography, X-Ray
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Disease Models, Animal
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Drug Interactions
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Escherichia coli / drug effects
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Escherichia coli / isolation & purification
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Humans
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Inhibitory Concentration 50
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Male
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Mice
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Microbial Sensitivity Tests
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Molecular Sequence Data
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Mycobacterium smegmatis / drug effects
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Nucleic Acid Conformation
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Protein Biosynthesis / drug effects
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RNA, Ribosomal, 16S / chemistry
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RNA, Ribosomal, 16S / genetics
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Ribosomes / metabolism
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Sepsis / drug therapy
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Staphylococcus aureus / drug effects
Substances
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Aminoglycosides
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Anti-Bacterial Agents
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RNA, Ribosomal, 16S
Associated data
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PDB/4B3M
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PDB/4B3R
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PDB/4B3S
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PDB/4B3T