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

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 XieBuchang Zhang, Yuanying Jiang, Xueting Liu, Richard Calderone, Fan Bai*, Lixin Zhang*, Gil Alterovitz

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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Abstract

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 by reversing the function of drug efflux pumps. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to multidrug resistance. 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 (MST) 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.
Original languageEnglish
JournalScience Bulletin
Volume66
Issue number18
Pages (from-to)1895-1905
Number of pages11
ISSN2095-9273
DOIs
Publication statusPublished - 2021

Keywords

  • Berberine
  • Candida albicans
  • Drug excretion transporter
  • Mitochondria
  • Multidrug-resistance

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