2. Academic Validation
  3. Discovery and Structural Optimization of Spirodioxynaphthalene-Based Mdr1 Efflux Pump Inhibitor to Combat Azole Resistance in Candida albicans

Discovery and Structural Optimization of Spirodioxynaphthalene-Based Mdr1 Efflux Pump Inhibitor to Combat Azole Resistance in Candida albicans

  • J Med Chem. 2026 Feb 12;69(3):3434-3456. doi: 10.1021/acs.jmedchem.5c03455.
Wenge Zhang 1,  Jinyao Chen 1,  Min Fang 1,  Minghui Song 1,  Zongxu Gao 1,  Jingru Hao 1,  Zejun Xu 1,  Xiuyun Li 2,  Shicun Zheng 2,  Wenqiang Chang 3,  Hongxiang Lou 1 4 2
Affiliations

Affiliations

  • 1 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Qilu Hospital, Shandong University, Jinan 250012, China.
  • 2 Infection and Microbiology Research Laboratory for Women and Children, Shandong Provincial Maternal and Child Health Care Hospital, Jinan 250014, China.
  • 3 Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), and State Key Laboratory of Microbial Technology, School of Pharmaceutical Sciences, Qilu Hospital, Shandong University, Jinan 250012, China.
  • 4 Joint Research Institute of Medical and Pharmaceutical Sciences, Qilu Hospital of Shandong University, Jinan 250012, China.
PMID: 41536117 DOI: 10.1021/acs.jmedchem.5c03455
Abstract

Overexpression of efflux pump genes drives azole resistance in Candida albicans, highlighting the need for efflux pump inhibitors. We identified pleopcin A (PA), a novel spirodioxynaphthalene from Pleopunctum brunnescens, which reverses Mdr1-mediated azole resistance. To enhance potency, we achieved its first total synthesis and designed 82 derivatives via target-ligand analysis. Among them, PA36-2 emerged as the most potent lead compound, showing 64-fold greater activity than PA in combination with fluconazole against MDR1-overexpressing C. albicans strains. Mechanistic studies confirmed PA36-2 as a specific Mdr1 inhibitor. In addition, PA36-2 combined with fluconazole exhibited potent in vivo activity against Galleria mellonella and mice infected with MDR1-overexpressing C. albicans strain. These findings support further pharmaceutical investigation of the potential value of PA36-2 as an Mdr1 inhibitor for overcoming azole resistance in C. albicans infections.

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