Identification of distinct thiopeptide-antibiotic precursor lead compounds using translation machinery assays.
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.
Starosta
Agata L
AL
Gene Center and Department of Chemistry and Biochemistry, Ludwig-Maximilians University of Munich, Feodor Lynen Strasse 25, 81377 Munich, Germany.
Qin
Haiou
H
Mikolajka
Aleksandra
A
Leung
Gulice Y C
GY
Schwinghammer
Kathrin
K
Nicolaou
Kyriacos C
KC
Chen
David Y-K
DY
Cooperman
Barry S
BS
Wilson
Daniel N
DN
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
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