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

• 作者: 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
• 来源期刊: 科学通报（英文版）
• 年，卷（期）: 2021,（18）
• 所属期刊栏目: ARTICLES
• 页码范围: 1895-1905
• 页数: 11页
• 语种: 英文

摘要

Clinical use of antimicrobials faces great challenges from the emergence of multidrug-resistant patho-gens.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 counter-intuitive case of reversing MDR in C.albicans by using a natural product berberine to hijack the overex-pressed 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.