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ACS Infect Dis. 2017 May 12;3(5):368-377. doi: 10.1021/acsinfecdis.6b00214. Epub 2017 Apr 6.

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

Author information

1
Department of Chemistry, Wayne State University , Detroit, Michigan 48202, United States.
2
Institute of Medical Microbiology, University of Zurich , 8006 Zurich, Switzerland.
3
Organic Chemistry Laboratory, ETH Zurich , 8093 Zurich, Switzerland.

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.

KEYWORDS:

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

PMID:
28343384
PMCID:
PMC5526222
DOI:
10.1021/acsinfecdis.6b00214
[Indexed for MEDLINE]
Free PMC Article

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