N6', N6''', and O4' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity.

ABSTRACT: 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.

SUBMITTER: Sati GC 

PROVIDER: S-EPMC5526222 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature