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