Synergistic activity of magnolol with azoles and its possible antifungal mechanism against Candida albicans

AIM: The goal of this study was to investigate the synergic effects between magnolol and azoles, and the potential antifungal mechanisms. METHODS AND RESULTS: Microdilution checkerboard, time‐kill and agar diffusion assay were employed to evaluate the synergic effects between magnolol and fluconazol...

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Bibliographic Details
Published in:	Journal of applied microbiology 2015-04, Vol.118 (4), p.826-838
Main Authors:	Sun, L.‐M, Liao, K, Liang, S, Yu, P.‐H, Wang, D.‐Y
Format:	Article
Language:	eng
Subjects:	ABC transporters agar Antifungal Agents - pharmacology antifungal properties ATP‐binding cassette transporter Azoles - pharmacology Biosynthesis Biphenyl Compounds - pharmacology Candida albicans Candida albicans - drug effects Candida albicans - genetics Candida albicans - metabolism Drug resistance Drug Synergism efflux inhibition ergosterol Ergosterol - biosynthesis fluconazole Fluconazole - pharmacology Fungal Proteins - genetics Fungal Proteins - metabolism gene expression regulation genes Lignans - pharmacology magnolol Membrane Transport Proteins - genetics Membrane Transport Proteins - metabolism Microbiology multiple drug resistance mutants reverse transcriptase polymerase chain reaction Up-Regulation - drug effects Yeast
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Summary:	AIM: The goal of this study was to investigate the synergic effects between magnolol and azoles, and the potential antifungal mechanisms. METHODS AND 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. SIGNIFICANCE AND IMPACT OF THE STUDY: 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.
ISSN:	1364-5072 1365-2672