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

Syntheses of the 6′-<i>N</i>-(2-hydroxyethyl) and 1-<i>N</i>-(4-amino-2<i>S</i>-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-<i>N</i>-(4-amino-2<i>S</i>-hydroxybutyryl)-6′-<i>N</i>-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-<i>N</i>-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-<i>N</i>-(4-amino-2<i>S</i>-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′-<i>N</i>-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) aminoglycoside-modifying enzymes, while the 1-<i>N</i>-(4-amino-2<i>S</i>-hydroxybutyryl) modification overcomes resistance to the AAC(2′) class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates

Influence of 4′‑<i>O</i>‑Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin

A series of 20 4′-<i>O</i>-glycosides of the aminoglycoside antibiotic paromomycin were synthesized and evaluated for their ability to inhibit protein synthesis by bacterial, mitochondrial and cytosolic ribosomes. Target selectivity, i.e., inhibition of the bacterial ribosome over eukaryotic mitochondrial and cytosolic ribosomes, which is predictive of antibacterial activity with reduced ototoxicity and systemic toxicity, was greater for the equatorial than for the axial pyranosides, and greater for the d-pentopyranosides than for the l-pentopyranosides and d-hexopyranosides. In particular, 4′-<i>O</i>-β-d-xylopyranosyl paromomycin shows antibacterioribosomal activity comparable to that of paromomycin, but is significantly more selective showing considerably reduced affinity for the cytosolic ribosome and for the A1555G mutant mitochondrial ribosome associated with hypersusceptibility to drug-induced ototoxicity. Compound antibacterioribosomal activity correlates with antibacterial activity, and the ribosomally more active compounds show activity against <i>Escherichia coli</i>, <i>Klebsiella pneumonia</i>, <i>Enterobacter cloacae</i>, <i>Acinetobacter baumannii</i>, and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). The paromomycin glycosides retain activity against clinical strains of MRSA that are resistant to paromomycin, which is demonstrated to be a consequence of 4′-<i>O</i>-glycosylation blocking the action of 4′-aminoglycoside nucleotidyl transferases by the use of recombinant <i>E. coli</i> carrying the specific resistance determinant

Synthesis and Antiribosomal Activities of 4′‑<i>O</i>‑, 6′‑<i>O</i>‑, 4″‑<i>O</i>‑, 4′,6′‑<i>O</i>- and 4″,6″‑<i>O</i>-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2‑Deoxystreptamine Aminoglycoside Antibiotics

Chemistry for the efficient modification of the kanamycin class of 4,6-aminoglycosides at the 4′-position is presented. In all kanamycins but kanamycin B, 4′-<i>O</i>-alkylation is strongly detrimental to antiribosomal and antibacterial activity. Ethylation of kanamycin B at the 4″-position entails little loss of antiribosomal and antibacterial activity, but no increase of ribosomal selectivity. These results are contrasted with those for the 4,5-aminoglycosides, where 4′-<i>O</i>-alkylation of paromomycin causes only a minimal loss of activity but results in a significant increase in selectivity with a concomitant loss of ototoxicity