title: Isolation, structure elucidation, and biological activity of altersolanol P using Staphylococcus aureus fitness test based genome-wide screening.
abstract: Bacteria continue to evade existing antibiotics by acquiring resistance by various mechanisms, leading to loss of antibiotic effectiveness. To avoid an epidemic from infections of incurable drug-resistant bacteria, new antibiotics with new modes of action are desperately needed. Using a genome-wide mechanism of action-guided whole cell screening approach based on antisense Staphylococcus aureus fitness test technology, we report herein the discovery of altersolanol P (1), a new tetrahydroanthraquinone from an unknown fungus from the Hypocreales isolated from forest litter collected in Puerto Rico. The structure was elucidated by high-resolution mass spectrometry and 2D NMR spectroscopy. Relative stereochemistry was established by NOESY correlations, and absolute configuration was deduced by the application of MPA ester-based methodology. Observed (1)H and (13)C NMR shifts were well aligned with the corresponding chemical shifts predicted by DFT calculations. Altersolanol P exhibited Gram-positive antibacterial activity (MIC range 1-8 μg/mL) and inhibited the growth of Gram-negative Haemophilus influenzae (MIC 2 μg/mL). The isolation, structure elucidation, and antibacterial activity of altersolanol P are described.
authors.affiliation: Merck Research Laboratories , Rahway, New Jersey 07065 and Kenilworth, New Jersey 07033, United States.
authors.forename: John
authors.initials: J
authors.lastname: Ondeyka
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Buevich
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Williamson
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Jon D
authors.initials: JD
authors.lastname: Polishook
authors.forename: James
authors.initials: J
authors.lastname: Occi
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: Angela
authors.initials: A
authors.lastname: Basilio
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.forename: Michael A
authors.initials: MA
authors.lastname: Goetz
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D006999:Hypocreales / Q000737:chemistry*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011647:Puerto Rico; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000880:Anthraquinones; D000900:Anti-Bacterial Agents; C000589166:altersolanol P