Macrolides, ketolides, lincosamides and straptogramins

This group of antibacterials share their mechanism of action- disrupting function of the bacterial 50S ribosomal subunit and inhibiting protein synthesis.

Macrolides consist of a large lactone ring with several deoxy sugars. Erythromycin and clarithromycin are representative examples. These drugs bind to the 50S subunit, near the peptidyltransferase centre (PTC). Therefore, the growing peptide cannot “lean over” and is kept in the A site. The subsequent events, i.e. the shifting of the “uncharged” tRNA to E site and ribosomal sliding movement, will not occur. GI disturbances and rash are common. There are rare occurrences of cholestatic hepatitis. Erythromycin is also a P450 inhibitor. One use of erythromycin is against S. pneumoniae if there is penicillin allergy. Common mechanisms of resistance to macrolides include decreased drug permeability, active drug efflux and most important of all, ribosomal alteration. The 50S ribosomal subunit is methylated, and this affects not only macrolide binding but also that of lincosamides (i.e. clindamycin) and streptogramins. This type of resistance is therefore referred to as MLS B-type resistance. The MLS B-type resistance is widespread across many bacterial species.

Telithromycin is a ketolide based on macrolides, but with a ketone and carbamate group. The ketone group decreases its susceptibility to MLS B-type resistance and active drug efflux while the carbamate group increases binding strength to ribosome. Antibacterial spectrum of telithromycin is similar to macrolides, but with better potency. However, potentially fatal hepatoxicity has limited its use, and in some jurisdictions its use has been withdrawn. 

Streptogramins include pristinamycin, quinupristin/dalfopristin and virginiamycin. These are effective in the treatment of multidrug-resistant bacteria such as vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-resistant Enterococcus (VRE).