Isolation, structure elucidation and antibacterial activity of a new tetramic acid, ascosetin.

Autor:	Ondeyka JG; Merck Research Laboratories, Rahway, NJ 07065, USA., Smith SK; Merck Research Laboratories, Rahway, NJ 07065, USA., Zink DL; Merck Research Laboratories, Rahway, NJ 07065, USA., Vicente F; CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain., Basilio A; CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain., Bills GF; CIBE, Merck Sharp & Dohme de Espana, S. A. Josefa Valcárcel, Madrid, Spain., Polishook JD; Merck Research Laboratories, Rahway, NJ 07065, USA., Garlisi C; In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA., Mcguinness D; In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA., Smith E; In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA., Qiu H; In vitro Pharmacology, Merck Research Laboratories, Kenilworth, NJ 07033, USA., Gill CJ; Merck Research Laboratories, Rahway, NJ 07065, USA., Donald RG; Merck Research Laboratories, Rahway, NJ 07065, USA., Phillips JW; Merck Research Laboratories, Rahway, NJ 07065, USA., Goetz MA; Merck Research Laboratories, Rahway, NJ 07065, USA., Singh SB; Merck Research Laboratories, Rahway, NJ 07065, USA.
Jazyk:	angličtina
Zdroj:	The Journal of antibiotics [J Antibiot (Tokyo)] 2014 Jul; Vol. 67 (7), pp. 527-31. Date of Electronic Publication: 2014 Apr 02.
DOI:	10.1038/ja.2014.33
Abstrakt:	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.
Databáze:	MEDLINE
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