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The emergence of resistant  Candida albicans  has made clinical fluconazole (FLC) treatment difficult. Improving sensitivity to FLC is an effective way to treat resistant isolates. Berberine hydrochloride (BBH) is a commonly used traditional Chinese medicine with antimicrobial effects, especially in resistant isolates. We investigated the molecular mechanisms underlying BBH and FLC synergism on biofilm-positive FLC-resistant  C. albicans  inhibition. Checkerboard microdilution assays and time-kill assays showed a strong synergistic effect between BBH and FLC in resistant  C. albicans  isolates, causing a significant 32–512-fold reduction in minimum inhibitory concentrations. BBH combined with FLC inhibited intracellular FLC efflux due to key efflux pump gene  CDR1  downregulation, whereas FLC alone induced high  CDR1  transcription in resistant strains. Further, BBH + FLC inhibited yeast adhesion, morphological hyphae transformation, and biofilm formation by downregulating the hyphal-specific genes  ALS3 ,  HWP1 , and  ECE1 . BBH caused cytoplasmic Ca 2+  influx, while FLC alone did not induce high intracellular Ca 2+  levels. The vacuolar calcium channel gene  YVC1  was upregulated, while the vacuolar calcium pump gene  PMC1  was downregulated in the BBH + FLC and BBH alone groups. However, vacuolar calcium gene expression after FLC treatment was opposite in biofilm-positive FLC-resistant  C. albicans , which might explain why BBH induces Ca 2+  influx. These results demonstrate that BBH + FLC exerts synergistic effects to increase FLC sensitivity by regulating multiple targets in FLC-resistant  C. albicans . These findings further show that traditional Chinese medicines have multi-target antimicrobial effects that may inhibit drug-resistant strains. This study also found that the vacuolar calcium regulation genes  YVC1  and  PMC1  are key BBH + FLC targets which increase cytoplasmic Ca 2+  in resistant isolates, which might be critical for reversing biofilm-positive FLC-resistant  C. albicans .

Synergistic Effect of Berberine Hydrochloride and Fluconazole Against Candida albicans Resistant Isolates