Ribosomal drug resistance in mycobacteria

Protein synthesis is one of the most complex of the cell's basic biological processes. It consists of cycles of sequential steps: decoding and binding of aminoacyl-tRNA, peptide bond formation and translocation of the ribosome. Decoding and binding of aminoacyl-tRNA is largely a function of the small subunit of the ribosome (30S), while the large subunit (50S) catalyses the peptide bond formation. The decoding site, which contains the entry side for aminoacyl-tRNA (A site), includes several conserved regions of 16S rRNA held together in a complex higher-order structure. A wide range of antibiotics act by inhibiting protein synthesis, with many of these drugs interacting directly with ribosomes. Among these drugs, aminoglycosides, macrolides and tetracyclines have activity against mycobacteria. Early studies of mutations conferring antibiotic resistance on drugs affecting protein synthesis focused on the ribosomal proteins as possible target sites for interaction with antibiotics. More recently, it has been found that many antibiotics block the binding of chemical probes to specific nucleotides in the 16S and/or 23S rRNAs. The nucleotides protected are generally bases that are implicated in the process that are affected by these drugs or are adjacent to such bases, suggesting that the mode of action of these drugs may be to interfere directly with the function of highly conserved sites in rRNA. Mutations in rRNA genes that confer antibiotic resistance have been observed when a single set of rRNA genes is present, as in yeast mitochondria or plant chloroplasts. Sensitivity to drugs that act by inhibiting protein synthesis is frequently dominant over antibiotic resistance, and thus in eubacteria, which generally have several sets of rRNA genes, such mutants cannot be isolated as a result of acquired resistance.