Abstract
A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Carbamates / chemical synthesis*
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Carbamates / chemistry
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Carbamates / pharmacology
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Cell-Free System
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Drug Resistance, Multiple
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Erythromycin / analogs & derivatives*
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Erythromycin / chemical synthesis*
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Erythromycin / chemistry
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Erythromycin / pharmacology
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Haemophilus influenzae / drug effects
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Ketolides*
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Lung / microbiology
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Mice
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Models, Molecular
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Protein Biosynthesis
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Protein Synthesis Inhibitors / chemical synthesis*
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Protein Synthesis Inhibitors / chemistry
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Respiratory Tract Infections / drug therapy
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Respiratory Tract Infections / microbiology
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Respiratory Tract Infections / mortality
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Ribosomes / drug effects
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Ribosomes / genetics
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Staphylococcus aureus / drug effects
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Streptococcus pneumoniae / drug effects
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Streptococcus pneumoniae / ultrastructure
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Streptococcus pyogenes / drug effects
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Structure-Activity Relationship
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Transcription, Genetic
Substances
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Anti-Bacterial Agents
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Carbamates
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Ketolides
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Protein Synthesis Inhibitors
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Erythromycin
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cethromycin