title: Isolation, structure elucidation and antibacterial activity of a new tetramic acid, ascosetin.
abstract: The ever-increasing bacterial resistance to clinical antibiotics is making many drugs ineffective and creating significant treatment gaps. This can be only circumvented by the discovery of antibiotics with new mechanisms of action. We report here the identification of a new tetramic acid, ascosetin, from an Ascomycete using the Staphylococcus aureus fitness test screening method. The structure was elucidated by spectroscopic methods including 2D NMR and HRMS. Relative stereochemistry was determined by ROESY and absolute configuration was deduced by comparative CD spectroscopy. Ascosetin inhibited bacterial growth with 2-16 μg ml(-1) MIC values against Gram-positive strains including methicillin-resistant S. aureus. It also inhibited the growth of Haemophilus influenzae with a MIC value of 8 μg ml(-1). It inhibited DNA, RNA, protein and lipid synthesis with similar IC50 values, suggesting a lack of specificity; however, it produced neither bacterial membrane nor red blood cell lysis. It showed selectivity for bacterial growth inhibition compared with fungal but not mammalian cells. The isolation, structure and biological activity of ascosetin have been detailed here.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Smith
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.affiliation: CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.affiliation: CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Basilio
authors.affiliation: CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Garlisi
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Mcguinness
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith
authors.affiliation: In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors.forename: Hongchen
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Gill
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goetz
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D001203:Ascomycota / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D011760:Pyrrolidinones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D011760:Pyrrolidinones; C009435:tetramic acid