title: Synergy-directed fractionation of botanical medicines: a case study with goldenseal (Hydrastis canadensis).
abstract: It is often argued that the efficacy of herbal medicines is a result of the combined action of multiple constituents that work synergistically or additively. Determining the bioactive constituents in these mixtures poses a significant challenge. We have developed an approach to address this challenge, synergy-directed fractionation, which combines comprehensive mass spectrometry profiling with synergy assays and natural products isolation. The applicability of synergy-directed fractionation was demonstrated using the botanical medicine goldenseal (Hydrastis canadensis) as a case study. Three synergists from goldenseal were identified, sideroxylin, 8-desmethyl-sideroxylin, and 6-desmethyl-sideroxylin. These flavonoids synergistically enhance the antimicrobial activity of the alkaloid berberine (also a constituent of H. canadensis) against Staphylococcus aureus by inhibition of the NorA multidrug resistance pump. The flavonoids possess no inherent antimicrobial activity against S. aureus; therefore, they could have been missed using traditional bioactivity-directed fractionation. The flavonoid synergists are present at higher concentration in extracts from H. canadensis leaves, while the antimicrobial alkaloid berberine is present at higher levels in H. canadensis roots. Thus, it may be possible to produce an extract with optimal activity against S. aureus using a combination of goldenseal roots and leaves.
authors.affiliation: Department of Chemistry and Biochemistry, The University of North Carolina Greensboro, P.O. Box 26170, Greensboro, North Carolina 27402, USA.
authors.forename: Hiyas A
authors.initials: HA
authors.lastname: Junio
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Sy-Cordero
authors.forename: Keivan A
authors.initials: KA
authors.lastname: Ettefagh
authors.forename: Johnna T
authors.initials: JT
authors.lastname: Burns
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Micko
authors.forename: Tyler N
authors.initials: TN
authors.lastname: Graf
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Richter
authors.forename: Robert E
authors.initials: RE
authors.lastname: Cannon
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Nadja B
authors.initials: NB
authors.lastname: Cech
mesh_terms: D001426:Bacterial Proteins / Q000187:drug effects; D001600:Berberine Alkaloids / Q000494:pharmacology; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D039321:Hydrastis / Q000737:chemistry*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects; D009657:North Carolina; D018515:Plant Leaves / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D001426:Bacterial Proteins; D001600:Berberine Alkaloids; D005419:Flavonoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C561550:6-desmethyl-sideroxylin; C561551:8-desmethyl-sideroxylin; C561549:sideroxylin; C075040:NorA protein, Staphylococcus