Header

UZH-Logo

Maintenance Infos

Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin


Matsushita, Takahiko; Chen, Weiwei; Juskeviciene, Reda; Teo, Youjin; Shcherbakov, Dimitri; Vasella, Andrea; Böttger, Erik C; Crich, David (2015). Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin. Journal of the American Chemical Society, 137(24):7706-7717.

Abstract

A series of 20 4′-O-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′-O-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 Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (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′-O-glycosylation blocking the action of 4′-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.

Abstract

A series of 20 4′-O-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′-O-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 Escherichia coli, Klebsiella pneumonia, Enterobacter cloacae, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (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′-O-glycosylation blocking the action of 4′-aminoglycoside nucleotidyl transferases by the use of recombinant E. coli carrying the specific resistance determinant.

Statistics

Citations

8 citations in Web of Science®
7 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:29 May 2015
Deposited On:19 Jun 2015 13:11
Last Modified:08 Dec 2017 13:14
Publisher:American Chemical Society (ACS)
ISSN:0002-7863
Publisher DOI:https://doi.org/10.1021/jacs.5b02248
PubMed ID:26024064

Download

Full text not available from this repository.
View at publisher