2 research outputs found
Influence of 4ā²ā<i>O</i>āGlycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin
A series of 20 4ā²-<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,
4ā²-<i>O</i>-Ī²-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 4ā²-<i>O</i>-glycosylation
blocking the action of 4ā²-aminoglycoside nucleotidyl transferases
by the use of recombinant <i>E. coli</i> carrying the specific
resistance determinant
Synthesis and Antiribosomal Activities of 4ā²ā<i>O</i>ā, 6ā²ā<i>O</i>ā, 4ā³ā<i>O</i>ā, 4ā²,6ā²ā<i>O</i>- and 4ā³,6ā³ā<i>O</i>-Derivatives in the Kanamycin Series Indicate Differing Target Selectivity Patterns between the 4,5- and 4,6-Series of Disubstituted 2āDeoxystreptamine Aminoglycoside Antibiotics
Chemistry
for the efficient modification of the kanamycin class of 4,6-aminoglycosides
at the 4ā²-position is presented. In all kanamycins but kanamycin
B, 4ā²-<i>O</i>-alkylation is strongly detrimental
to antiribosomal and antibacterial activity. Ethylation of kanamycin
B at the 4ā³-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 4ā²-<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