Inhibition of RNase P RNA cleavage by aminoglycosides.
A number of aminoglycosides have been reported to interact and interfere with the function of various RNA molecules. Among these are 16S rRNA, the group I intron, and the hammerhead ribozymes. In this report we show that cleavage by RNase P RNA in the absence as well as in the presence of the RNase P protein is inhibited by several aminoglycosides. Among the ones we tested, neomycin B was found to be the strongest inhibitor with a Ki value in the micromolar range (35 microM). Studies of lead(II)-induced cleavage of RNase P RNA suggested that binding of neomycin B interfered with the binding of divalent metal ions to the RNA. Taken together, our findings suggest that aminoglycosides compete with Mg2+ ions for functionally important divalent metal ion binding sites. Thus, RNase P, which is an essential enzyme, is indeed a potential drug target that can be used to develop new drugs by using various aminoglycosides as lead compounds.
Mikkelsen
N E
NE
Department of Cell and Molecular Biology, Box 596, Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Brännvall
M
M
Virtanen
A
A
Kirsebom
L A
LA
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001483:Base Sequence; D001667:Binding, Competitive; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D005601:Framycetin / Q000494:pharmacology; D007612:Kanamycin / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D007854:Lead / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009174:Mycoplasma / Q000201:enzymology; D009690:Nucleic Acid Conformation; D010303:Paromomycin / Q000494:pharmacology; D012313:RNA / Q000378:metabolism*; D016337:RNA, Catalytic / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D043262:Ribonuclease P; D013379:Substrate Specificity; D014158:Transcription, Genetic
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D016337:RNA, Catalytic; D012336:RNA, Ribosomal, 16S; D011994:Recombinant Proteins; C001495:bekanamycin; D007854:Lead; D005601:Framycetin; D007612:Kanamycin; D010303:Paromomycin; D012313:RNA; D004722:Endoribonucleases; D043262:Ribonuclease P; C470865:ribonuclease P, E coli; D008274:Magnesium