Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA.

Yu L, Oost TK, Schkeryantz JM, Yang J, Janowick D, Fesik SW
J Am Chem Soc. 2003 125 (15): 4444-50

PMID: 12683814 · DOI:10.1021/ja021354o

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.

MeSH Terms (11)

Aminoglycosides Aminoquinolines Anti-Bacterial Agents Binding, Competitive Biomimetic Materials Escherichia coli Ligands Models, Molecular Nuclear Magnetic Resonance, Biomolecular RNA, Bacterial RNA, Ribosomal, 16S

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