N6 ', N6 ''', and 04 ' Modifications to Neomycin Affect Ribosomal Selectivity without Compromising Antibacterial Activity

作者：Sati Girish C; Shcherbakov Dimitri; Hobbie Sven N; Vasella Andrea^*; Bottger Erik C^*; Crich David^*

来源：ACS Infectious Diseases, 2017, 3(5): 368-377.

DOI：10.1021/acsinfecdis.6b00214

• aminoglycosides
• ototoxicity
• multidrug-resistant infectious diseases
• decoding A site
• cell-free translation assay
• synthesis

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'-0-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'-0-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.

• 出版日期2017-5
• 单位河北医科大学