title: Synergistic activity of magnolol with azoles and its possible antifungal mechanism against Candida albicans.
abstract: OBJECTIVE
  The goal of this study was to investigate the synergic effects between magnolol and azoles, and the potential antifungal mechanisms.
  
  
  RESULTS
  Microdilution checkerboard, time-kill and agar diffusion assay were employed to evaluate the synergic effects between magnolol and fluconazole (FLC). Magnolol significantly decreased the efflux of rhodamine 123 (Rh123), leading to greater intracellular accumulation of Rh123 in Candida albicans cells. Compared to the Candida drug resistance (cdr) 2 or multidrug resistance (mdr) 1 deletion mutant, the growth of cdr1 strain was most sensitive to magnolol exposure. In the presence of magnolol, MDR1 overexpressing cells were sensitive to FLC, whereas CDR1 and CDR2 overexpressing cells displayed tolerance to FLC. Magnolol treatment correlated with up-regulation of transporter and ergosterol biosynthesis pathway genes, analyzed by real-time reverse transcription-polymerase chain reaction. The ergosterol content of C. albicansSC5314 was significantly decreased after magnolol exposure.
  
  
  CONCLUSIONS
  Magnolol synergizes with azoles for targeting of C. albicans by inducing a higher intracellular content of antifungals, by tapping into the competitive effect of ABC transporter Cdr1p substrates, and enhancing the effect by targeting of the ergosterol biosynthesis pathway.
  
  
  CONCLUSIONS
  Our results provide the first evidence that magnolol may function as a Cdr1p substrate and as an inhibitor of ergosterol biosynthesis. This function can thus be exploited in combination with azoles to reverse multidrug resistance of C. albicans strains.
authors: Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
authors: L-M
authors: LM
authors: Sun
authors: K
authors: K
authors: Liao
authors: S
authors: S
authors: Liang
authors: P-H
authors: PH
authors: Yu
authors: D-Y
authors: DY
authors: Wang
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D001713:Biphenyl Compounds; D005656:Fungal Proteins; D017705:Lignans; D026901:Membrane Transport Proteins; C005498:magnolol; D015725:Fluconazole; D004875:Ergosterol
keywords: ATP-binding cassette transporter; Candida albicans; efflux inhibition; ergosterol; fluconazole; magnolol