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

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.