title: Influence of 4'-O-Glycoside Constitution and Configuration on Ribosomal Selectivity of Paromomycin.
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.
authors.affiliation: †Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: †Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.affiliation: ‡Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland.
authors.forename: Reda
authors.initials: R
authors.lastname: Juskeviciene
authors.affiliation: ‡Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Teo
authors.affiliation: ‡Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Shcherbakov
authors.affiliation: §Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasella
authors.affiliation: ‡Institut für Medizinische Mikrobiologie, Universität Zürich, 8006 Zürich, Switzerland.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.affiliation: †Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States.
authors.forename: David
authors.initials: D
authors.lastname: Crich
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000166:cytology / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008968:Molecular Conformation; D010303:Paromomycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012270:Ribosomes / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D010303:Paromomycin