Rational design of azepane-glycoside antibiotics targeting the bacterial ribosome.
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.
Barluenga
Sofia
S
Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc, 9050 Camino Santa Fe, San Diego, CA 92121, USA.
Simonsen
Klaus B
KB
Littlefield
Ethel S
ES
Ayida
Benjamin K
BK
Vourloumis
Dionisios
D
Winters
Geoffrey C
GC
Takahashi
Masayuki
M
Shandrick
Sarah
S
Zhao
Qiang
Q
Han
Qing
Q
Hermann
Thomas
T
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
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001381:Azepines; D006027:Glycosides; D006571:Heterocyclic Compounds; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D010303:Paromomycin