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    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. Copyright © 2020 Science China Press. Published by Elsevier B.V. All rights reserved.


    Yaojun Tong, Jingyu Zhang, Nuo Sun, Xiang-Ming Wang, Qi Wei, Yu Zhang, Ren Huang, Yingying Pu, Huanqin Dai, Biao Ren, Gang Pei, Fuhang Song, Guoliang Zhu, Xinye Wang, Xuekui Xia, Xiangyin Chen, Lan Jiang, Shenlin Wang, Liming Ouyang, Ning Xie, Buchang Zhang, Yuanying Jiang, Xueting Liu, Richard Calderone, Fan Bai, Lixin Zhang, Gil Alterovitz. Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p. Science bulletin. 2021 Sep 30;66(18):1895-1905

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    PMID: 36654399

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