Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris

Yuping Zhang, Lingbing Zeng, Xinhua Huang, Yuanyuan Wang, Guangsheng Chen, Munika Moses, Yun Zou, Sichu Xiong, Wenwen Xue, Yanmei Dong, Yueru Tian, Ming Guan, Lingfei Hu, Zhe Yin, Dongsheng Zhou (), Xiaotian Huang () and Changbin Chen ()
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Yuping Zhang: Nanchang University
Lingbing Zeng: Nanchang University
Xinhua Huang: Chinese Academy of Sciences
Yuanyuan Wang: Chinese Academy of Sciences
Guangsheng Chen: Chinese Academy of Sciences
Munika Moses: Chinese Academy of Sciences
Yun Zou: Chinese Academy of Sciences
Sichu Xiong: Chinese Academy of Sciences
Wenwen Xue: Nanjing Advanced Academy of Life and Health
Yanmei Dong: Tianjin Key Laboratory of Hepatopancreatic Fiberosis and Molecular Diagnosis & Treatment
Yueru Tian: Fudan University
Ming Guan: Fudan University
Lingfei Hu: Academy of Military Medical Sciences
Zhe Yin: Academy of Military Medical Sciences
Dongsheng Zhou: Academy of Military Medical Sciences
Xiaotian Huang: Nanchang University
Changbin Chen: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The rise of drug-resistant fungal species, such as Candida auris, poses a serious threat to global health, with mortality rates exceeding 40% and resistance rates surpassing 90%. The limited arsenal of effective antifungal agents underscores the urgent need for novel strategies. Here, we systematically evaluate the role of histone H3 post-translational modifications in C. auris drug resistance, focusing on acetylation mediated by Gcn5 and Rtt109, and methylation mediated by Set1, Set2, and Dot1. Mutants deficient in these enzymes exhibit varying degrees of antifungal drug sensitivity. Notably, we discover that GCN5 depletion and the subsequent loss of histone H3 acetylation downregulates key genes involved in ergosterol biosynthesis and drug efflux, resulting in increased susceptibility to azoles and polyenes. Additionally, Gcn5 regulates cell wall integrity and echinocandin resistance through the calcineurin signaling pathway and transcription factor Cas5. In infection models using Galleria mellonella and immunocompromised mice, GCN5 deletion significantly reduces the virulence of C. auris. Furthermore, the Gcn5 inhibitor CPTH2 synergizes with caspofungin in vitro and in vivo without notable toxicity. These findings highlight the critical role of Gcn5 in the resistance and pathogenicity of C. auris, positioning it as a promising therapeutic target for combating invasive fungal infections.

Date: 2025
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DOI: 10.1038/s41467-025-59898-6

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