N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity.
The synthesis of a series of neomycin derivatives carrying the 2-hydroxyethyl substituent on N6' and/or N6‴ both alone and in combination with a 4'-O-ethyl group is described. By means of cell-free translation assays with wild-type bacterial ribosomes and their hybrids with eukaryotic decoding A sites, we investigate how individual substituents and their combinations affect activity and selectivity at the target level. In principle, and as shown by cell-free translation assays, modifications of the N6' and N6‴ positions allow enhancement of target selectivity without compromising antibacterial activity. As with the 6'OH aminoglycoside paromomycin, the 4'-O-ethyl modification affects the ribosomal activity, selectivity, and antibacterial profile of neomycin and its 6'-N-(2-hydroxyethyl) derivatives. The modified aminoglycosides show good antibacterial activity against model Gram-positive and Gram-negative microbes including the ESKAPE pathogens Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter cloacae, and Acinetobacter baumannii.
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
Girish C
GC
Sati
Institute of Medical Microbiology, University of Zurich , 8006 Zurich, Switzerland.
Dimitri
D
Shcherbakov
Institute of Medical Microbiology, University of Zurich , 8006 Zurich, Switzerland.
Sven N
SN
Hobbie
Organic Chemistry Laboratory, ETH Zurich , 8093 Zurich, Switzerland.
Andrea
A
Vasella
Institute of Medical Microbiology, University of Zurich , 8006 Zurich, Switzerland.
Erik C
EC
Böttger
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
David
0000-0003-2400-0083
D
Crich
D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020029:Base Pairing; D001483:Base Sequence; D002236:Carbohydrate Conformation; D016972:Enterobacter cloacae / Q000187:drug effects / Q000254:growth & development; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D009355:Neomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010303:Paromomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D000900:Anti-Bacterial Agents; D010303:Paromomycin; D009355:Neomycin
aminoglycosides; cell-free translation assay; decoding A site; multidrug-resistant infectious diseases; ototoxicity; synthesis