Synonymous codon bias as a basis for novel antibiotic design: from nucleotide wobble constraint to ribosomal garrotte

The observation of low guanine frequencies at wobble position codons over Rossmann-fold GXGXXG motifs, led to the discovery of sequence-wide synonymous codon bias, from this we propose novel ribosomal inhibitors. Methodology & results: The wobble bases of multiple sequence alignments of diverse Rossmann-fold enzymes were counted, A, C, T and G wobble frequencies of consecutive codons were displayed as wobble plots. Synonymous codon constraints were found throughout the length of proteins, particularly at Rossmann folds. Prokaryote mRNAs have disallowed nucleotide sequences with wobble bases, evolutionary tailored to safeguard translation. We propose one such editing mechanism ensures that glycine motifs avoid becoming Shine-Dalgarno motifs.

We propose using peptide nucleic acids and cyclic peptidyl scaffolds as a means of presenting disallowed chemical interactions to the anti-Shine-Dalgarno.