title: Toxicity modulation, resistance enzyme evasion, and A-site X-ray structure of broad-spectrum antibacterial neomycin analogs.
abstract: Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs.
authors.affiliation: Department of Chemistry, Université de Montréal , CP 6128 Succ. Centre-Ville, Montréal, Québec H3C3J7, Canada.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Maianti
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kanazawa
authors.forename: Paola
authors.initials: P
authors.lastname: Dozzo
authors.forename: Rowena D
authors.initials: RD
authors.lastname: Matias
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Feeney
authors.forename: Eliana S
authors.initials: ES
authors.lastname: Armstrong
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Hildebrandt
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Kane
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Gliedt
authors.forename: Adam A
authors.initials: AA
authors.lastname: Goldblum
authors.forename: Martin S
authors.initials: MS
authors.lastname: Linsell
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.forename: Jiro
authors.initials: J
authors.lastname: Kondo
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanessian
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009355:Neomycin / Q000031:analogs & derivatives*; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D012313:RNA; D009355:Neomycin