Inhibition of translation and bacterial growth by peptide nucleic acid targeted to ribosomal RNA.
Peptide nucleic acid (PNA) is a DNA mimic that has shown considerable promise as a lead compound for developing gene therapeutic drugs. We report that PNAs targeted to functional and accessible sites in ribosomal RNA can inhibit translation in an Escherichia coli cell-free transcription/translation system, with 50% reductions caused by nanomolar PNA concentrations. The effect in vitro is quantitatively similar to that of the known translation inhibitor and antibiotic tetracycline. Also, the targeted PNAs inhibited bacterial growth on agar plates and in liquid culture. A strain of E. coli (AS19) that is more permeable to antibiotics was approximately 10-fold more sensitive to the active PNAs, suggesting that the effect on growth indeed was caused by PNAs that entered cells. Inhibition was not observed when using control PNAs of similar composition but with an unrelated or mismatched sequence. The results demonstrate that ribosomal RNA is a possible target for sequence-designed novel antibiotics based on DNA analogues or mimics.
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Center for Biomolecular Recognition, Departments of Medical Biochemistry and Genetics, Biochemistry B, The Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Copenhagen, Denmark.
Nielsen
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D001483:Base Sequence; D001665:Binding Sites; D002474:Cell-Free System; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012329:RNA, Bacterial / Q000187:drug effects / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects*
D019384:Nucleic Acid Synthesis Inhibitors; D016376:Oligonucleotides, Antisense; D012329:RNA, Bacterial; D012335:RNA, Ribosomal