title: Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor.
abstract: Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.
authors.affiliation: Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Stermitz
authors.forename: P
authors.initials: P
authors.lastname: Lorenz
authors.forename: J N
authors.initials: JN
authors.lastname: Tawara
authors.forename: L A
authors.initials: LA
authors.lastname: Zenewicz
authors.forename: K
authors.initials: K
authors.lastname: Lewis
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001599:Berberine / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004357:Drug Synergism; D004996:Ethidium / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D005453:Fluorescence; D006801:Humans; D008564:Membrane Potentials; D008954:Models, Biological; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010946:Plants, Medicinal / Q000737:chemistry*; D012838:Silymarin / Q000031:analogs & derivatives*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001599:Berberine; D004996:Ethidium; D005419:Flavonoids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012838:Silymarin; C405502:5'-methoxyhydnocarpin; C075040:NorA protein, Staphylococcus