title: Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase.
abstract: BACKGROUND
  Baicalein, the active constituent derived from Scutellaria baicalensis Georgi., has previously been shown to significantly restore the effectiveness of β-lactam antibiotics and tetracycline against methicillin-resistant Staphylococcus aureus (MRSA). With multiple therapeutic benefits, the antibacterial actions of baicalein may also be involved in overcoming other bacterial resistance mechanisms. The aim of the present study was to further investigate antibacterial activities of baicalein in association with various antibiotics against selected Staphylococcus aureus strains with known specific drug resistance mechanisms.
  
  
  METHODS
  A panel of clinical MRSA strains was used for further confirmation of the antibacterial activities of baicalein. The effect of baicalein on inhibiting the enzymatic activity of a newly discovered MRSA-specific pyruvate kinase (PK), which is essential for Staphylococcus aureus growth and survival was also examined.
  
  
  RESULTS
  In the checkerboard dilution test and time-kill assay, baicalein at 16 μg/ml could synergistically restore the antibacterial actions of ciprofloxacin against the NorA efflux pump overexpressed SA-1199B, but not with the poor NorA substrate, pefloxacin. Moreover, synergistic effects were observed when baicalein was combined with ciprofloxacin against 12 out of 20 clinical ciprofloxacin resistant strains. For MRSA PK studies, baicalein alone could inhibit the enzymatic activity of MRSA PK in a dose-dependent manner.
  
  
  CONCLUSIONS
  Our results demonstrated that baicalein could significantly reverse the ciprofloxacin resistance of MRSA possibly by inhibiting the NorA efflux pump in vitro. The inhibition of MRSA PK by baicalein could lead to a deficiency of ATP which might further contribute to the antibacterial actions of baicalein against MRSA.
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ben C L
authors.initials: BC
authors.lastname: Chan
authors.forename: Margaret
authors.initials: M
authors.lastname: Ip
authors.forename: Clara B S
authors.initials: CB
authors.lastname: Lau
authors.forename: S L
authors.initials: SL
authors.lastname: Lui
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.forename: Carine
authors.initials: C
authors.lastname: Ganem-Elbaz
authors.forename: Marc
authors.initials: M
authors.lastname: Litaudon
authors.forename: Neil E
authors.initials: NE
authors.lastname: Reiner
authors.forename: Huansheng
authors.initials: H
authors.lastname: Gong
authors.forename: Raymond H
authors.initials: RH
authors.lastname: See
authors.forename: K P
authors.initials: KP
authors.lastname: Fung
authors.forename: P C
authors.initials: PC
authors.lastname: Leung
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002939:Ciprofloxacin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D004791:Enzyme Inhibitors; D044950:Flavanones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011770:Pyruvate Kinase; C075040:NorA protein, Staphylococcus; C006680:baicalein