The context of the ribosome binding site in mRNAs defines specificity of action of kasugamycin, an inhibitor of translation initiation

Abstract

Significance Several antibiotics targeting the large ribosomal subunit interfere with translation in a context-specific manner, preventing ribosomes from polymerizing specific amino acid sequences. Here, we reveal kasugamycin as a small ribosomal subunit-targeting antibiotic whose action depends on the sequence context of the untranslated messenger RNA (mRNA) segments. We show that kasugamycin-induced ribosomal arrest at the start codons of the genes and the resulting inhibition of gene expression depend on the nature of the mRNA nucleotide immediately preceding the start codon and on the proximity of the stop codon of the upstream cistron. Our findings underlie the importance of mRNA context for the action of protein synthesis inhibitors and might help to guide the development of better antibiotics.