Structure-activity relationships and mechanism of action of macrolides derived from erythromycin as antibacterial agents.

Enormous efforts were focused on the 3-descladinosyl erythromycin derivatives which led to 3-keto (ketolides), 3-O-acyl (acylides), 3-O-carbamate (carbamolides), and 3-O-alkyl (alkylides) and cladinosyl-containing erythromycin derivatives such as 4"-O-acyl, 4"-O-carbamate, and 4"-O-alkyl derivatives as recently exemplified by macrolones (macrolide-quinolone hybrids). Ketolides acquire activity against MLSB-resistant pathogens via a featured arylalkyl extension suspended on the macrolide core, which interacts with a base pair formed by A752Ec and U2609Ec located in the nascent peptide release tunnel of the bacterial rRNA. A base pair formed by C2610Ec and G2505Ec probably is another novel binding site for 3-descladinosyl non-ketolides. It is believed that 4"-derived compounds perhaps interfere with the formation of polypeptide because the extension oriented into peptidyl transferase center (PTC) region. Although macrolones are hybrids of macrolides and quinolones, they do not have dual modes of action, and serve only as protein synthesis inhibitors.