title: Identification of distinct thiopeptide-antibiotic precursor lead compounds using translation machinery assays.
abstract: Most thiopeptide antibiotics target the translational machinery: thiostrepton (ThS) and nosiheptide (NoS) target the ribosome and inhibit translation factor function, whereas GE2270A/T binds to the elongation factor EF-Tu and prevents ternary complex formation. We have used several in vitro translational machinery assays to screen a library of thiopeptide antibiotic precursor compounds and identified four families of precursor compounds that are either themselves inhibitory or are able to relieve the inhibitory effects of ThS, NoS, or GE2270T. Some of these precursors represent distinct compounds with respect to their ability to bind to ribosomes. The results not only provide insight into the mechanism of action of thiopeptide compounds but also demonstrate the potential of such assays for identifying lead compounds that might be missed using conventional inhibitory screening protocols.
authors.affiliation: Gene Center and Department of Chemistry and Biochemistry, Ludwig-Maximilians University of Munich, Feodor Lynen Strasse 25, 81377 Munich, Germany.
authors.forename: Agata L
authors.initials: AL
authors.lastname: Starosta
authors.forename: Haiou
authors.initials: H
authors.lastname: Qin
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mikolajka
authors.forename: Gulice Y C
authors.initials: GY
authors.lastname: Leung
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwinghammer
authors.forename: Kyriacos C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: David Y-K
authors.initials: DY
authors.lastname: Chen
authors.forename: Barry S
authors.initials: BS
authors.lastname: Cooperman
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Wilson
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020558:GTP Phosphohydrolases / Q000378:metabolism; D010444:Peptide Elongation Factor Tu / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D013883:Thiostrepton / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C520601:GE2270T; D010456:Peptides, Cyclic; D011355:Prodrugs; D013844:Thiazoles; D020558:GTP Phosphohydrolases; D010444:Peptide Elongation Factor Tu; C014134:nosiheptide; D013883:Thiostrepton