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Updated: May 6, 2026
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Discovery and Structural Optimization of Spirodioxynaphthalene-Based Mdr1 Efflux Pump Inhibitor to Combat Azole
Wenge Zhang1, Jinyao Chen1, Min Fang1
1Department 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.
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.
