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
State Key Laboratory of Bioreactor Engineering and School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100190, China; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
State Key Laboratory of Bioreactor Engineering and School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China.
Sci Bull (Beijing). 2021 Sep 30;66(18):1895-1905. doi: 10.1016/j.scib.2020.12.035. Epub 2020 Dec 31.
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.
抗菌药物的临床应用面临着多重耐药病原体出现带来的巨大挑战。药物外排泵的过度表达是导致多重耐药（MDR）的主要因素之一。逆转药物外排泵的功能是克服多重耐药的一种有前景的方法。在危及生命的真菌病原体白色念珠菌中，主要易化子超家族（MFS）转运蛋白Mdr1p可以排出许多结构不相关的抗真菌药物，导致多重耐药。在此，我们报告了一个违反直觉的案例，即通过使用天然产物黄连素劫持过度表达的Mdr1p来实现自身的导入，从而逆转白色念珠菌的多重耐药。此外，我们证明导入的黄连素在线粒体中积累，并通过损害线粒体膜电位和线粒体复合体I来损害线粒体功能。这导致选择性消除过度表达Mdr1p的白色念珠菌细胞。此外，我们表明黄连素治疗可以延长患有血行播散的过度表达Mdr1p的多重耐药念珠菌病小鼠的平均存活时间。这项研究通过筛选多重耐药外排泵转化剂为新型抗多重耐药药物的发现提供了一个潜在方向。
