title: Tobramycin Variants with Enhanced Ribosome-Targeting Activity.
abstract: With the increased evolution of aminoglycoside (AG)-resistant bacterial strains, the need to develop AGs with 1) enhanced antimicrobial activity, 2) the ability to evade resistance mechanisms, and 3) the capability of targeting the ribosome with higher efficiency is more and more pressing. The chemical derivatization of the naturally occurring tobramycin (TOB) by attachment of 37 different thioether groups at the 6''-position led to the identification of generally poorer substrates of TOB-targeting AG-modifying enzymes (AMEs). Thirteen of these displayed better antibacterial activity than the parent TOB while retaining ribosome-targeting specificity. Analysis of these compounds in vitro shed light on the mechanism by which they act and revealed three with clearly enhanced ribosome-targeting activity.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY 40536-0596 (USA).
authors.forename: Marina Y
authors.initials: MY
authors.lastname: Fosso
authors.affiliation: Department of Microbiology, Center for RNA Biology, Ohio State University, 484 W. 12th Avenue, Columbus, OH 43210-1292 (USA).
authors.forename: Hongkun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY 40536-0596 (USA).
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington, KY 40536-0596 (USA). sylviegtsodikova@uky.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.affiliation: Department of Microbiology, Center for RNA Biology, Ohio State University, 484 W. 12th Avenue, Columbus, OH 43210-1292 (USA). fredrick.5@osu.edu.
authors.forename: Kurt
authors.initials: K
authors.lastname: Fredrick
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D012270:Ribosomes / Q000187:drug effects*; D014031:Tobramycin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D014031:Tobramycin
keywords: aminoglycoside; antibacterial agents; bacterial resistance; drug-modifying enzymes; translocation