title: Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.
abstract: A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.
authors.affiliation: Pharmaceutical Discovery Division, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6098, USA. liping.yu@abbott.com
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Thorsten K
authors.initials: TK
authors.lastname: Oost
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Schkeryantz
authors.forename: Jianguo
authors.initials: J
authors.lastname: Yang
authors.forename: Dave
authors.initials: D
authors.lastname: Janowick
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000378:metabolism; D000634:Aminoquinolines / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D012329:RNA, Bacterial / Q000737:chemistry* / Q000378:metabolism; D012336:RNA, Ribosomal, 16S / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000634:Aminoquinolines; D000900:Anti-Bacterial Agents; D008024:Ligands; D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S