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Modification at the 2'-Position of the 4,5-Series of 2-Deoxystreptamine Aminoglycoside Antibiotics To Resist Aminoglycoside Modifying Enzymes and Increase Ribosomal Target Selectivity.

Authors
  • Sati, Girish C1
  • Sarpe, Vikram A1
  • Furukawa, Takayuki1
  • Mondal, Sujit1
  • Mantovani, Matilde2
  • Hobbie, Sven N2
  • Vasella, Andrea3
  • Böttger, Erik C2
  • Crich, David1
  • 1 Department of Chemistry , Wayne State University , 5101 Cass Avenue , Detroit , Michigan 48202 , United States. , (United States)
  • 2 Institute of Medical Microbiology , University of Zurich , 28 Gloriastrasse , 8006 Zürich , Switzerland. , (Switzerland)
  • 3 Organic Chemistry Laboratory , ETH Zürich , Vladimir-Prelog-Weg 1-5/10 , 8093 Zürich , Switzerland. , (Switzerland)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Oct 11, 2019
Volume
5
Issue
10
Pages
1718–1730
Identifiers
DOI: 10.1021/acsinfecdis.9b00128
PMID: 31436080
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

A series of derivatives of the 4,5-disubstituted class of 2-deoxystreptamine aminoglycoside antibiotics neomycin, paromomycin, and ribostamycin was prepared and assayed for (i) their ability to inhibit protein synthesis by bacterial ribosomes and by engineered bacterial ribosomes carrying eukaryotic decoding A sites, (ii) antibacterial activity against wild type Gram negative and positive pathogens, and (iii) overcoming resistance due to the presence of aminoacyl transferases acting at the 2'-position. The presence of five suitably positioned residual basic amino groups was found to be necessary for activity to be retained upon removal or alkylation of the 2'-position amine. As alkylation of the 2'-amino group overcomes the action of resistance determinants acting at that position and in addition results in increased selectivity for the prokaryotic over eukaryotic ribosomes, it constitutes an attractive modification for introduction into next generation aminoglycosides. In the neomycin series, the installation of small (formamide) or basic (glycinamide) amido groups on the 2'-amino group is tolerated.

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