2. Academic Validation
  3. Exporter Mdr1 as an importer is an achilles' heel for combating drug-resistant Candida

Exporter Mdr1 as an importer is an achilles' heel for combating drug-resistant Candida

  • Cell Chem Biol. 2026 Feb 19;33(2):227-240.e6. doi: 10.1016/j.chembiol.2026.01.009.
Jinyao Chen 1,  Ming Zhang 2,  Yeji Wang 1,  Zhiyu Xie 3,  Fei Yang 1,  Hongjun Yu 4,  Di Zhang 4,  Min Fang 1,  Xiaoyi Luan 1,  Xueyang Jin 1,  Xue Wang 1,  Yanan Qiao 1,  Shicun Zheng 5,  Xiuyun Li 5,  Wenqiang Chang 6,  Hongxiang Lou 7
Affiliations

Affiliations

  • 1 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 2 Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 3 Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, College of Chemical and Materials Engineering, Xuchang University, Xuchang, Henan, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Shandong Provincial Maternal and Child Care Hospital, Jinan, Shandong, China.
  • 6 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong Province, China. Electronic address: [email protected].
  • 7 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Joint Research Institute of Medical and Pharmaceutical Sciences, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 41720080 DOI: 10.1016/j.chembiol.2026.01.009
Abstract

The overexpression of drug exporters is a well-known mechanism driving Antifungal drug resistance. Here, we investigate that converting the exporter to function as a drug importer provides an alternative approach to combat drug resistance. Using high-throughput screening, we identified quaternary ammonium compounds exhibiting hypersensitivity in Candida albicans strains overexpressing MDR1. Further experiments involving CRISPR-Cas9-mediated deletion in C. albicans, heterologous expression of CaMdr1 in Saccharomyces cerevisiae and construction of CaMdr1-containing proteoliposomes confirmed Mdr1 acts as an importer of MKT-077, a potent cyanine derivative highly selective against MDR1-overexpressing strains. By combining computational simulations and the site-directed mutagenesis, critical residues within the transmembrane domains of CaMdr1 involved in MKT-077 import were further identified. Moreover, MKT-077 exhibited therapeutic efficacy in Galleria mellonella infected with Mdr1-overexpressing C. albicans. This work opens an avenue to convert drug resistance into drug sensitivity-a paradigm-shifting strategy in Antifungal drug discovery.

Keywords

Candida; azole resistance; cyanine derivative; drug importer; efflux pump.

Figures
Products