title: Molecular mechanism of action of virginiamycin-like antibiotics (synergimycins) on protein synthesis in bacterial cell-free systems.
abstract: Synergimycins contain two types of components, A and B, which synergistically inhibit in-vivo protein synthesis. In-vitro, both components interact with 50 s ribosomal subunits. B components bind in stoichiometric amounts (KA = 2.5 X 10(6) M-1): the association constant undergoes a ten-fold increase in the presence of A components. The latter inhibitors act in substoichiometric concentration (KA = 0.32 X 10(6) M-1) and produce lasting ribosome damage due to a conformational alteration requiring proteins L7/L12, L8 and L16. Such alteration entails a permanent block of the peptidyltransferase substrate acceptor site, whereby aminoacyl tRNA enzymically bound to ribosomes is released. Macrolides (KA = 7.2 X 10(7) M-1) displace ribosome-bound B components, but they are unable to compete in the presence of A components, which reduce both the affinity of ribosomes for macrolides, and the dissociation rate constant of B components. These findings provide a molecular explanation to the synergistic action of A and B components in-vivo.
mesh_terms: D001419:Bacteria / Q000187:drug effects / Q000235:genetics*; D002413:Cations, Divalent; D002414:Cations, Monovalent; D002474:Cell-Free System; D004917:Erythromycin / Q000494:pharmacology; D007700:Kinetics; D014176:Protein Biosynthesis / Q000187:drug effects*; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014769:Virginiamycin / Q000494:pharmacology*
chemical_list: D002413:Cations, Divalent; D002414:Cations, Monovalent; D012346:RNA, Transfer, Amino Acyl; D014769:Virginiamycin; D004917:Erythromycin