title: Structure-guided discovery of novel aminoglycoside mimetics as antibacterial translation inhibitors.
abstract: We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.
authors.affiliation: Anadys Pharmaceuticals, San Diego, California, USA.
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Vlad E
authors.initials: VE
authors.lastname: Gregor
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Sun
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Ayida
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Winters
authors.forename: Douglas
authors.initials: D
authors.lastname: Murphy
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Simonsen
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
authors.forename: Sarah
authors.initials: S
authors.lastname: Fish
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Froelich
authors.forename: Daniel
authors.initials: D
authors.lastname: Wall
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects*; D011487:Protein Conformation; D012270:Ribosomes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014227:Triazines / Q000494:pharmacology
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D010880:Piperidines; D014227:Triazines