title: Synergy of streptogramin antibiotics occurs independently of their effects on translation.
abstract: Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically. We compared the molecular interactions of the streptogramin combinations Synercid (type A, dalfopristin; type B, quinupristin) and NXL 103 (type A, flopristin; type B, linopristin) with the Escherichia coli 70S ribosome by X-ray crystallography. We further analyzed the activity of the streptogramin components individually and in combination. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. Notably, the diethylaminoethylsulfonyl group in dalfopristin reduces its activity but is the basis for synergy in transcription-coupled translation assays before its rapid hydrolysis from the depsipeptide core. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for synergy. The absence of general streptogramin synergy in transcription-coupled translation assays suggests that the synergistic antimicrobial activity of streptogramins can occur independently of the effects of streptogramin on translation.
authors: Department of Molecular Cell Biology, California Institute of Quantitative Biosciences, University of California, Berkeley, California, USA.
authors: Jonas
authors: J
authors: Noeske
authors: AstraZeneca R&D Boston, Discovery Sciences, Waltham, Massachusetts, USA.
authors: Jian
authors: J
authors: Huang
authors: AstraZeneca R&D Boston, Discovery Sciences, Waltham, Massachusetts, USA.
authors: Nelson B
authors: NB
authors: Olivier
authors: AstraZeneca R&D Boston, Infection Innovative Medicines Unit, Waltham, Massachusetts, USA.
authors: Robert A
authors: RA
authors: Giacobbe
authors: AstraZeneca R&D Boston, Infection Innovative Medicines Unit, Waltham, Massachusetts, USA.
authors: Mark
authors: M
authors: Zambrowski
authors: Department of Molecular Cell Biology, California Institute of Quantitative Biosciences, University of California, Berkeley, California, USA jcate@lbl.gov.
authors: Jamie H D
authors: JH
authors: Cate
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D004338:Drug Combinations; D004357:Drug Synergism; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects / Q000648:ultrastructure; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D025364:Streptogramin A / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D025381:Streptogramin B / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D025361:Streptogramins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D014769:Virginiamycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D025361:Streptogramins; C509060:flopristin, linopristin drug combination; D014769:Virginiamycin; C062940:quinupristin-dalfopristin; D025381:Streptogramin B; D025364:Streptogramin A