Antibiotic inhibitors of protein synthesis on the ribosome

Abstract

Many types of chemically diverse antibiotics inhibit bacterial growth by binding to the ribosome and blocking protein synthesis. The large majority of these antibiotics have a distinct target site on either the 30S or the 50S ribosomal subunit. Thus, these antibiotics are generally specific inhibitors of steps in protein synthesis that are associated with either the 30S subunit (such as mRNA decoding) or the 50S subunit (such as peptide bond formation or controlled GTP hydrolysis). An important exception to this rule is the cyclic peptide drug, capreomycin, which is currently used to treat strains of Mycobacterium tuberculosis that have become resistant to first‐line drug therapy. Capreomycin and related drugs function by binding across the ribosomal subunit interface to simultaneously interact with both the 30S and the 50S, where they block the translocation of tRNA along the messenger RNA. Resistance to many ribosome‐targeting drugs is often conferred by addition of one or more methyl groups to specific nucleotides in the rRNA, and thereby sterically hindering the binding of the antibiotic to its target. Resistance to capreomycin has been analyzed in clinical strains of M. tuberculosis, and the mechanism is exceptional in that it is conferred by loss of natural methylations on the rRNA, rather than by gaining extra methylations.