Tandem gene duplications contributed to high-level azole resistance in a rapidly expanding Candida tropicalis population

Xin Fan; Rong-Chen Dai; Shu Zhang; Yuan-Yuan Geng; Mei Kang; Da-Wen Guo; Ya-Ning Mei; Yu-Hong Pan; Zi-Yong Sun; Ying-Chun Xu; Jie Gong; Meng Xiao

doi:10.1038/s41467-023-43380-2

Tandem gene duplications contributed to high-level azole resistance in a rapidly expanding Candida tropicalis population

Nat Commun. 2023 Dec 15;14(1):8369. doi: 10.1038/s41467-023-43380-2.

Authors

Xin Fan^#^{1

2}, Rong-Chen Dai^#^{2

3}, Shu Zhang^{3

4}, Yuan-Yuan Geng^{3

4}, Mei Kang⁵, Da-Wen Guo⁶, Ya-Ning Mei⁷, Yu-Hong Pan⁸, Zi-Yong Sun⁹, Ying-Chun Xu¹⁰, Jie Gong^{11

12}, Meng Xiao¹³

Affiliations

¹ Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
² Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
³ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
⁴ Peking University First Hospital - National Institute for Communicable Disease Control and Prevention Joint Laboratory of Pathogenic Fungi, Beijing, 102206, China.
⁵ Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
⁶ Department of Clinical Laboratory, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
⁷ Department of Clinical Laboratory, Jiangsu Province Hospital, Nanjing, 210029, Jiangsu, China.
⁸ Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
⁹ Department of Clinical Laboratory, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
¹⁰ Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China. xycpumch@139.com.
¹¹ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China. gongjie@icdc.cn.
¹² Peking University First Hospital - National Institute for Communicable Disease Control and Prevention Joint Laboratory of Pathogenic Fungi, Beijing, 102206, China. gongjie@icdc.cn.
¹³ Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China. cjtcxiaomeng@aliyun.com.

^# Contributed equally.

Abstract

Invasive diseases caused by the globally distributed commensal yeast Candida tropicalis are associated with mortality rates of greater than 50%. Notable increases of azole resistance have been observed in this species, particularly within Asia-Pacific regions. Here, we carried out a genetic population study on 1571 global C. tropicalis isolates using multilocus sequence typing (MLST). In addition, whole-genome sequencing (WGS) analysis was conducted on 629 of these strains, comprising 448 clinical invasive strains obtained in this study and 181 genomes sourced from public databases. We found that MLST clade 4 is the predominant azole-resistant clone. WGS analyses demonstrated that dramatically increasing rates of azole resistance are associated with a rapid expansion of cluster AZR, a sublineage of clade 4. Cluster AZR isolates exhibited a distinct high-level azole resistance, which was induced by tandem duplications of the ERG11^A395T gene allele. Ty3/gypsy-like retrotransposons were found to be highly enriched in this population. The alarming expansion of C. tropicalis cluster AZR population underscores the urgent need for strategies against growing threats of antifungal resistance.

MeSH terms

Antifungal Agents* / pharmacology
Azoles* / pharmacology
Candida tropicalis / genetics
Drug Resistance, Fungal / genetics
Gene Duplication
Microbial Sensitivity Tests
Multilocus Sequence Typing

Substances

Azoles
Antifungal Agents

Grants and funding

81802042/National Natural Science Foundation of China (National Science Foundation of China)