Fluconazole assists berberine to kill fluconazole-resistant Candida albicans

De Dong Li, Yi Xu, Da Zhi Zhang, Hua Quan, Eleftherios Mylonakis, Dan Dan Hu, Ming Bang Li, Lan Xue Zhao, Liang Hua Zhu, Yan Wang, Yuan Ying Jiang

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.

Original languageEnglish (US)
Pages (from-to)6016-6027
Number of pages12
JournalAntimicrobial Agents and Chemotherapy
Volume57
Issue number12
DOIs
StatePublished - Dec 2013

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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