Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

[Display omitted] Berberine harnesses the multidrug efflux pump Mdr1 of pathogenic fungus Candida albicans for its own importation and accumulation, it then targets mitochondria and interrupts the electron transfer chain (ETC) to specifically kill the Mdr1 overexpressed C. albicans cells. Clinical u...

Full description

Saved in:
Bibliographic Details
Published in:Science bulletin (Beijing) 2021-09, Vol.66 (18), p.1895-1905
Main Authors: Tong, Yaojun, Zhang, Jingyu, Sun, Nuo, Wang, Xiang-Ming, Wei, Qi, Zhang, Yu, Huang, Ren, Pu, Yingying, Dai, Huanqin, Ren, Biao, Pei, Gang, Song, Fuhang, Zhu, Guoliang, Wang, Xinye, Xia, Xuekui, Chen, Xiangyin, Jiang, Lan, Wang, Shenlin, Ouyang, Liming, Xie, Ning, Zhang, Buchang, Jiang, Yuanying, Liu, Xueting, Calderone, Richard, Bai, Fan, Zhang, Lixin, Alterovitz, Gil
Format: Article
Language:English
Subjects:
Berberine
Candida albicans
Drug excretion transporter
Mitochondria
Multidrug-resistance
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] Berberine harnesses the multidrug efflux pump Mdr1 of pathogenic fungus Candida albicans for its own importation and accumulation, it then targets mitochondria and interrupts the electron transfer chain (ETC) to specifically kill the Mdr1 overexpressed C. albicans cells. Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant pathogens. The overexpression of drug efflux pumps is one of the major contributors to multidrug resistance (MDR). Reversing the function of drug efflux pumps is a promising approach to overcome MDR. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to MDR. Here we report a counterintuitive case of reversing MDR in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. This results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time of mice with blood-borne dissemination of Mdr1p overexpressed multidrug-resistant candidiasis. This study provides a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.
ISSN:2095-9273
DOI:10.1016/j.scib.2020.12.035