Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms

Ying Peng, Yan Lu, Hui Sun, Jinying Ma, Xiaomei Li, Xiaodan Han, Zhixiong Fang, Junming Tan, Yingchen Qiu, Tingting Qu, Meng Yin () and Zhaofeng Yan ()
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Ying Peng: Hunan University
Yan Lu: Hunan University
Hui Sun: Hunan University
Jinying Ma: Tsinghua University
Xiaomei Li: Shanxi Academy of Advanced Research and Innovation
Xiaodan Han: Hunan University
Zhixiong Fang: Hunan University
Junming Tan: Hunan University
Yingchen Qiu: Hunan University
Tingting Qu: Hunan University
Meng Yin: Hunan University
Zhaofeng Yan: Hunan University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1Apo), fluconazole-bound state (Cdr1Flu), and milbemycin oxime-inhibited state (Cdr1Mil). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.

Date: 2024
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DOI: 10.1038/s41467-024-52107-w

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