Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6′-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics

Syntheses of the 6′-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6′-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6′-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) aminoglycoside-modifying enzymes,...