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Abstract
The 16S rRNA binding mechanism proposed for the antibacterial action of the tetracyclines does not explain their mechanism of action against non-bacterial pathogens. In addition, several contradictory base pairs have been proposed as their binding sites on the 16S rRNA. This study investigated the binding of minocycline and doxycycline to short double-stranded RNAs (dsRNAs) of random base sequences. These tetracyclines caused a dose-dependent decrease in the fluorescence intensities of 6-carboxyfluorescein (FAM)-labelled dsRNA and ethidium bromide (EtBr)-stained dsRNA, indicating that both drugs bind to dsRNA of random base sequence in a manner that is competitive with the binding of EtBr and other nucleic acid ligands often used as stains. This effect was observable in the presence of Mg(2+). The binding of the tetracyclines to dsRNA changed features of the fluorescence emission spectra of the drugs and the CD spectra of the RNA, and inhibited RNase III cleavage of the dsRNA. These results indicate that the double-stranded structures of RNAs may have a more important role in their interaction with the tetracyclines than the specific base pairs, which had hitherto been the subject of much investigation. Given the diverse functions of cellular RNAs, the binding of the tetracyclines to their double-stranded helixes may alter the normal processing and functioning of the various biological processes they regulate. This could help to explain the wide range of action of the tetracyclines against various pathogens and disease conditions.
Highlights
The tetracyclines are a group of broad-spectrum antibiotics that are known to act by inhibiting the binding of aminoacyl-tRNA to the mRNA–ribosome complex, thereby inhibiting protein synthesis.1,2 They are generally believed to bind to the 16S ribosomal RNA, which is composed of a 1540 nucleotide RNA
This study investigated the binding of minocycline and doxycycline to short double-stranded RNAs of random base sequences
To investigate the nature of these interactions, the experiments were repeated using the non-labelled 27-bp double-stranded RNAs (dsRNAs) of random sequence, and the gel was stained with ethidium bromide (EtBr) after electrophoresis
Summary
The tetracyclines are a group of broad-spectrum antibiotics that are known to act by inhibiting the binding of aminoacyl-tRNA to the mRNA–ribosome complex, thereby inhibiting protein synthesis. They are generally believed to bind to the 16S ribosomal RNA, which is composed of a 1540 nucleotide RNA. The tetracyclines are a group of broad-spectrum antibiotics that are known to act by inhibiting the binding of aminoacyl-tRNA to the mRNA–ribosome complex, thereby inhibiting protein synthesis.. The tetracyclines are a group of broad-spectrum antibiotics that are known to act by inhibiting the binding of aminoacyl-tRNA to the mRNA–ribosome complex, thereby inhibiting protein synthesis.1,2 They are generally believed to bind to the 16S ribosomal RNA, which is composed of a 1540 nucleotide RNA. In addition to their use as antibacterial agents, the tetracyclines are known to be effective in the treatment of non-bacterial infections; for example, in the treatment of protozoan diseases such as giardiasis and viral diseases such as West Nile fever.. In addition to their use as antibacterial agents, the tetracyclines are known to be effective in the treatment of non-bacterial infections; for example, in the treatment of protozoan diseases such as giardiasis and viral diseases such as West Nile fever. They possess anti-inflammatory, anti-apoptotic and neuroprotective properties. There is little indication of the mechanism(s) of action that underlie many of the reported activities. Because of the similarities between the bacterial ribosome and mitochondrial ribosome, it was believed that the anti-protozoal activities of the tetracyclines were mediated via a similar interaction with the mitochondrial ribosome of these parasites. the susceptibility of other protozoan species that lack mitochondria (for example, Trichomonas vaginalis, Giardia lamblia and Entamoeba histolytica) as well as viruses and helminths raises further questions about the exact target site(s) and molecular mechanism(s) of action of the tetracyclines
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