title: Singly modified amikacin and tobramycin derivatives show increased rRNA A-site binding and higher potency against resistant bacteria.
abstract: Semisynthetic derivatives of the clinically useful aminoglycosides tobramycin and amikacin were prepared by selectively modifying their 6'' positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa, Klebsiella pneumonia, MRSA) were quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogues displayed higher affinity for the bacterial A-site than the parent compounds. Although most tobramycin analogues exhibited no improvement in antibacterial activity, several amikacin analogues showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.
authors: Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA).
authors: Richard J
authors: RJ
authors: Fair
authors: Lisa S
authors: LS
authors: McCoy
authors: Mary E
authors: ME
authors: Hensler
authors: Bernice
authors: B
authors: Aguilar
authors: Victor
authors: V
authors: Nizet
authors: Yitzhak
authors: Y
authors: Tor
mesh_terms: D000583:Amikacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D012336:RNA, Ribosomal, 16S / Q000187:drug effects*; D014031:Tobramycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D012336:RNA, Ribosomal, 16S; D000583:Amikacin; D014031:Tobramycin
keywords: A-site rRNA; aminoglycosides; antibiotics; drug-resistant bacteria