title: Discovery of okilactomycin and congeners from Streptomyces scabrisporus by antisense differential sensitivity assay targeting ribosomal protein S4.
abstract: Protein synthesis inhibition is a highly successful target for developing clinically effective and safe antibiotics. There are several targets within the ribosomal machinery, and small ribosomal protein S4 (RPSD) is one of the newer targets. Screening of microbial extracts using antisense-sensitized rpsD Staphylococcus aureus strain led to isolation of okilactomycin and four new congeners from Streptomyces scabrisporus. The major compound, okilactomycin, was the most active, with a minimum detection concentration of 3-12 microg ml(-1) against antisense assay, and showed an MIC of 4-16 microg ml(-1) against Gram-positive bacteria, including S. aureus. The congeners were significantly less active in all assays, and all compounds showed a slight preferential inhibition of RNA synthesis over DNA and protein synthesis. Antisense technology, due to increased sensitivity, continues to yield new, even though weakly active, antibiotics.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Chaowei
authors.initials: C
authors.lastname: Zhang
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Angela
authors.initials: A
authors.lastname: Basilio
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Oscar
authors.initials: O
authors.lastname: Salazar
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Karen
authors.initials: K
authors.lastname: Dorso
authors.forename: Mary
authors.initials: M
authors.lastname: Motyl
authors.forename: Kevin
authors.initials: K
authors.lastname: Byrne
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D001419:Bacteria / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005285:Fermentation; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008826:Microbial Sensitivity Tests; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010802:Phylogeny; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012336:RNA, Ribosomal, 16S / Q000096:biosynthesis / Q000235:genetics; D012269:Ribosomal Proteins / Q000187:drug effects* / Q000235:genetics*; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D013302:Streptomyces / Q000145:classification / Q000235:genetics* / Q000378:metabolism*
chemical_list: D007783:Lactones; D019384:Nucleic Acid Synthesis Inhibitors; D016376:Oligonucleotides, Antisense; D011500:Protein Synthesis Inhibitors; D012336:RNA, Ribosomal, 16S; D012269:Ribosomal Proteins; C031798:ribosomal protein S4; C054471:okilactomycin