Practice question

Macrolides such as erythromycin, azithromycin and clarithromycin belong to group characterized by large 14-, 15- or 16-membered lactone rings decorated with deoxy sugar moieties L-cladinose and desosamine that confer binding specificity. They lodge within the nascent peptide exit tunnel of the large ribosomal subunit. Bacterial ribosomes comprise small 30S and large 50S subunits; 50S contains 23S rRNA that forms the peptidyl transferase center and tunnel spanning subunit. Macrolides bind at nucleotides 2058 and 2059 of domain V of 23S rRNA near the peptidyl transferase center, partially occluding the tunnel with sugar moieties projecting inward. Peptide chain elongation proceeds for a few amino acids until steric hindrance prevents translocation of peptidyl-tRNA from A to P site, causing premature dissociation of incomplete peptidyl-tRNA and halting protein synthesis. This halts translation in a selective manner leaving DNA synthesis and folate metabolism untouched and producing bacteriostatic effect at low concentrations. Methylation of adenine at A2058 by erm methylases encoded by ermB confers high-level resistance of MLS-B phenotype, highlighting precise molecular contact point and explaining cross-resistance to lincosamides and streptogramin B.