The streptogramin antibiotics: update on their mechanism of action

Antibiotics of the streptogramin class are an association of two types of chemically different compounds, group A molecules and group B molecules, acting in synergy. The combination of these molecules generally inhibits bacterial growth at a lower concentration than does either the group A or group B molecule alone and is often bactericidal against strains of bacteria for which each type of molecule alone is only bacteriostatic. The semisynthetic streptogramin quinupristin/dalfopristin (RP 59500), the first water-soluble member of this class, is under development for the treatment of severe infections caused by methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, glycopeptide-resistant Enterococcus faecium, and other organisms. The streptogramins block the translation of mRNA into protein. Both group A and group B molecules bind to the peptidyl-transferase domain of the bacterial ribosome. The group B molecule stimulates the dissociation of peptidyl-tRNA from the ribosome and may interfere with the passage of the completed polypeptide away from the peptidyl-transferase centre. The group A molecule inhibits the elongation of the polypeptide chain by preventing both the binding of aminoacyl-tRNA to the ribosomal A site and the formation of the peptide bond. When the two types of molecule are used in combination, the binding of the group A molecule alters the conformation of the ribosome such that the affinity of the ribosome for the B molecule is increased. This accounts, in part or entirely, for the observed synergy. This synergy is unaffected by ribosomal modifications conferring resistance to the macrolides, lincosamides, and group B molecules alone.