Journal Article

Synergistic Antifungal Activity of Berberine Derivative B-7b and Fluconazole

Liu, Wei, Qi, Yun Peng, Cao, Xin Ju, Yan, Lan, He, Li Juan, Liu, Hong, Zhang, Shi Qun, An, Mao Mao, Zhang, Jun Dong, Huang, Xin, Zhu, Fang, Chen, Si Min, Jiang, Yuan Ying, Li, Li Ping, Shen, Hui, Zhang, Da Zhi, Xu, Zheng

2015

Overview

Our previous study demonstrated berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. We also suggested BBR played a major antifungal role in the synergism of FLC and BBR, while FLC increased intracellular BBR concentrations. Our following systematic structural modification and reconstruction of BBR core identified the novel scaffold of N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(substituted phenyl)acet-amide derivatives 7a-i, including B-7b and B-7d exhibiting remarkable synergistic antifungal activity and low cytotoxicity. Here, the study mainly investigated the synergistic activity of FLC and B-7b and the underlying mechanism. In vitro interaction of FLC and B-7b was investigated against 30 FLC-resistant clinical isolates of C. albicans and non-C. albicans species, including Candida tropicalis, Candida parapsilosis, Candida glabrata, Candida krusei and Cryptococcus neoformans. The potent synergistic activity of B-7b in combination with FLC against FLC-resistant C. albicans was found through the checkerboard microdilution assay. The findings of agar diffusion tests and time-kill curves confirmed its better synergism with FLC. And as expected, B-7b exhibited much lower cytotoxicity than BBR to human umbilical vein endothelial cells. In contrast to BBR, we found that endogenous ROS augmentation was not involved in the synergism of FLC and B-7b. According to the results from our present comparative proteomic study, it seemed that the disruption of protein folding and processing and the weakening of cells' self-defensive ability contributed to the synergism of FLC and B-7b. Together, these results suggested novel scaffold BBR derivative B-7b could be a promising synergist in combination with FLC for the treatment of invasive fungal infections.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Agar / Alcohol / Antifungal activity / Antifungal agents / Antifungal Agents - pharmacology / Antimicrobial agents / Augmentation / Berberine / Berberine - pharmacology / Candida - drug effects / Candida albicans / Candida krusei / Candida parapsilosis / Cell cycle / Clinical isolates / Cryptococcus neoformans / Cryptococcus neoformans - drug effects / Cytotoxicity / Dehydrogenases / Diffusion tests / Drug Resistance, Fungal / Drug Synergism / Endothelial cells / Fluconazole / Fluconazole - pharmacology / Fungicides / Genes / Hospitals / Hydrastis canadensis / Infections / Medicine / Microbial Sensitivity Tests / Pharmacology / Pharmacy / Protein folding / Proteins / R&D / Research & development / RNA polymerase / Saccharomyces cerevisiae / Synergism / Toxicity / Umbilical vein / Yeast