Structure–activity relationships of ketolides vs. macrolides

Since their discovery, the macrolide antimicrobials have proved clinically valuable for the treatment of respiratory tract infections, offering coverage against a broad spectrum of pathogens and excellent tolerability. However, the global increase in macrolide resistance among respiratory pathogens, particularly Streptococcus pneumoniae, threatens their future usefulness. The ketolides, of which telithromycin is the first to reach clinical development, represent a new generation of antimicrobials that have been developed with a view to overcoming the problem of macrolide resistance. Telithromycin is structurally derived from macrolides, and possesses several distinguishing features that are important for its improved microbiological profile. The L-cladinose at position C3 of the macrolactone ring has been replaced with a keto function. This modification enables telithromycin to bind to its target without tripping the inducible resistance to macrolide–lincosamide–streptograminB (MLSB) drugs that many groups of pathogens exhibit. The C6 position has been modified by the addition of a methoxy group. This helps prevent hemiketalization of the C6 position with the 3- and 9-keto groups, thereby conferring excellent acid stability, particularly at gastric pH values. Telithromycin is differentiated from other ketolide compounds by the addition of a large aromatic N-substituted carbamate extension from positions C11/C12. This carbamate extension improves binding of the drug to its target, the 50S ribosomal subunit, as demonstrated in in vitro experiments. Telithromycin binds to wild-type ribosomes with 10-fold greater affinity than erythromycin A and 6-fold greater affinity than clarithromycin; its affinity for MLSB-resistant ribosomes is > 20 times that of both macrolides. The increased ribosomal affinity of telithromycin correlates with its superior potency against Gram-positive cocci both in vitro and in vivo, and is one of the factors determining the drug's activity against MLSB-resistant respiratory pathogens