A
method is described for the NMR-based screening for the discovery of a
minoglycoside
mi
meticsthat bind to
Escherichia coli A-site RNA. Although a
minoglycosides are clinically useful, they exhibit highnephrotoxicity and ototoxicity, and their overuse has led to the develop
ment of resistance to i
mportant
microbial pathogens. To identify a new series of a
minoglycoside
mi
metics that could potentially overco
methe proble
ms associated with toxicities and resistance develop
ment observed with the a
minoglycosides,we have prepared large quantities of
E. coli 16 S A-site RNA and conducted an NMR-based screening ofour co
mpound library in search for s
mall-
molecule RNA binders against this RNA target. Fro
m these studies,several classes of co
mpounds were identified as initial hits with binding affinities in the range of 70
![](/i<font color=)
mages/entities/
mgr.gif">M to3
mM. Lead opti
mization through synthetic
modifications of these initial hits led to the discovery of severals
mall-
molecule a
minoglycoside
mi
metics that are structurally very different fro
m the known a
minoglycosides.Structural
models of the A-site RNA/ligand co
mplexes were prepared and co
mpared to the three-di
mensionalstructures of the RNA/a
minoglycoside co
mplexes.