4′-O-substitutions determine selectivity of aminoglycoside antibiotics

Abstract

Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4′,6′-O-acetal and 4′-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4′-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets.

Structural basis for the inhibition of the eukaryotic ribosome

“…5c). This finding confirms previous results on low inhibitory activity of aminoglycosides in eukaryotes 31 . In line with this, most kanamycins and all gentamicins contain an amino group or a carbon side chain at this position responsible for their limited effect on the eukaryotic ribosome.…”

In Vivo Efficacy of Apramycin in Murine Infection Models

“…The in vivo efficacy of apramycin as a broad-range antibacterial agent was tested in a neutropenic model of Staphylococcus aureus septicemia (21). The animal experiments were carried out at Euprotec Limited, Manchester, United Kingdom, under United Kingdom Home Office Licenses, with ethical approval from the University of Manchester Ethics committee.…”

Evidence That Antibiotics Bind to Human Mitochondrial Ribosomal RNA Has Implications for Aminoglycoside Toxicity

“…Modification of ring I has been found to decrease off-site binding to human cytoplasmic and mitochondrial ribosomes without reducing the antibacterial activity against the bacterial ribosome (49). The selectivity of paromamine-derived aminoglycosides depends on the structural context of nucleosides 1408 (A for bacterial and mitochondrial and G for cytoplasmic) and 1491 (G for bacterial, C for mitochondrial, and A for cytoplasmic) (49).…”

“…One of the most prevalent toxic side effects of aminoglycosides, ototoxicity, is linked to A1555G and C1949U mutations of eukaryotic mitochondrial ribosomes (49). NMR results indicated that analogous residues of E. coli H69 and hmt69 experienced the most significant chemical shift perturbation upon aminoglycoside binding with one important exception.…”

“…In the CD spectra, an increasing ellipticity at base regions of H69 indicated increased base stacking, which is highly correlated to the thermal stability established by aminoglycoside binding. The 2-DOS-containing paromaminederived aminoglycosides, such as kanamycin A and gentamicin, have been known to form a pseudo-base pair or stack with bases of H44 (49). Also, these aminoglycosides interact with phosphate groups of H44 and stabilize the position of ring I (49).…”