Synergism Of Fluconazole And Berberine Against Clinical Isolates Of Candida Albicans Resistant To Fluconazole

Multidrug resistance aggravates treatment failure of invasive infections with C. albicans, a most common Candida pathogen. Few were reported about combination therapy against C. albicans resistant to fluconazole (FLC). Berberine chloride (BBR), a natural compound, has low host toxicity. We investigated the synergic effect in vitro between FLC and BBR against FLC-resistant C. albicans by checkerboard microdilution assay (FICI<0.5). Agar disk diffusion test, time-kill curve studies and experiments in vivo confirmed the synergism of FLC and BBR against FLC-resistant C. albicans. The combination produced the accumulations of lanosterol and the other sterol. After treated with the combination, isolates have been seen that some material accumulated around cell membrane, and cell cycle arrest at S phase. No significant effect from BBR occurred at the active efflux of rhodamine 6G by CDR1, but MDR1 was up-regulated by BBR. BBR dramatically promoted the production of intra-cellular reactive oxygen species (ROS) with dose-dependent mode. Based on cDNA microarray, the express of a crop of genes have changed after the treatment of FLC combined with BBR. Down-regulated genes were related with transport proteins, RNA processing, translation initiation factor and so on. Up-regulated genes included the genes about mitochondrial respiratory, oxidative stress, dehydrogenase, and nucleotide excision repair.