Targeting epigenetic regulators to overcome drug resistance in the emerging human fungal pathogen Candida auris
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 CPTH<sub>2</sub> 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.
Authors
- Yueru Tian
- Xiaotian Huang (ORCID: https://orcid.org/0000-0003-1145-8386)
- Changbin Chen (ORCID: https://orcid.org/0000-0002-7961-3488)
- Lingbing Zeng (ORCID: https://orcid.org/0000-0001-7196-0955)
- Ming Guan (ORCID: https://orcid.org/0000-0002-8861-1281)
- Yun Zou
- Zhe Yin (ORCID: https://orcid.org/0000-0003-0530-7100)
- Dongsheng Zhou (ORCID: https://orcid.org/0000-0003-3827-5969)
- Lingfei Hu (ORCID: https://orcid.org/0000-0001-7287-6800)
- Yuanyuan Wang (ORCID: https://orcid.org/0000-0001-7464-7446)
- Yuping Zhang (ORCID: https://orcid.org/0000-0003-1055-2071)
- Wenwen Xue
- Yanmei Dong (ORCID: https://orcid.org/0000-0002-9154-8949)
- Guang-Sheng Chen (ORCID: https://orcid.org/0000-0002-2468-4190)
- Xinhua Huang
- Munika Moses
- Sichu Xiong
Institutions
- Fudan University (CN)
- Academy of Military Medical Sciences (CN)
- Jiangsu Academy of Agricultural Sciences (CN)
- Chinese People's Armed Police Force Medical College Affiliated Hospital (CN)
- First Affiliated Hospital of Jiangxi Medical College (CN)
- Huashan Hospital (CN)
- Institute of Infection and Immunity (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-59898-6
- Citations
- 17
- Primary Topic
- Antifungal resistance and susceptibility
- Type
- article
- Field-Weighted Citation Impact
- 23.73
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Government of Jiangsu Province
- Fudan University
- Nanchang University
- Stockholms Universitet
- Science for Life Laboratory
- Huashan Hospital
- Recruitment Program of Global Experts
- State Key Laboratory of Pathogen and Biosecurity
- Institute of Microbiology, Chinese Academy of Sciences