title: Rational design of azepane-glycoside antibiotics targeting the bacterial ribosome.
abstract: RNA recognition by natural aminoglycoside antibiotics depends on the 2-deoxystreptamine (2-DOS) scaffold which participates in specific hydrogen bonds with the ribosomal decoding-site target. Three-dimensional structure information has been used for the design of azepane-monoglycosides, building blocks for novel antibiotics in which 2-DOS is replaced by a heterocyclic scaffold. Azepane-glycosides showed target binding and translation inhibition in the low micromolar range and inhibited growth of Staphylococcus aureus, including aminoglycoside-resistant strains.
authors.affiliation: Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc, 9050 Camino Santa Fe, San Diego, CA 92121, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.forename: Klaus B
authors.initials: KB
authors.lastname: Simonsen
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Littlefield
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Ayida
authors.forename: Dionisios
authors.initials: D
authors.lastname: Vourloumis
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Winters
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Sarah
authors.initials: S
authors.lastname: Shandrick
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Qing
authors.initials: Q
authors.lastname: Han
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermann
mesh_terms: D000617:Aminoglycosides / Q000009:adverse effects / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006027:Glycosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D010303:Paromomycin; D014176:Protein Biosynthesis / Q000187:drug effects; D012329:RNA, Bacterial / Q000037:antagonists & inhibitors; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001381:Azepines; D006027:Glycosides; D006571:Heterocyclic Compounds; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D010303:Paromomycin