Hotspot mutations and genomic expansion of ERG11 are major mechanisms of azole resistance in environmental and human commensal isolates of Candida tropicalis

Tianren Hu; Sijia Wang; Jian Bing; Qiushi Zheng; Han Du; Chao Li; Zhangyue Guan; Feng-Yan Bai; Clarissa J Nobile; Haiqing Chu; Guanghua Huang

doi:10.1016/j.ijantimicag.2023.107010

Hotspot mutations and genomic expansion of ERG11 are major mechanisms of azole resistance in environmental and human commensal isolates of Candida tropicalis

Int J Antimicrob Agents. 2023 Dec;62(6):107010. doi: 10.1016/j.ijantimicag.2023.107010. Epub 2023 Oct 18.

Authors

Tianren Hu¹, Sijia Wang², Jian Bing², Qiushi Zheng², Han Du³, Chao Li², Zhangyue Guan¹, Feng-Yan Bai⁴, Clarissa J Nobile⁵, Haiqing Chu⁶, Guanghua Huang⁷

Affiliations

¹ Department of Infectious Diseases, Huashan Hospital, Shanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai, China.
² Department of Infectious Diseases, Huashan Hospital, Shanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
³ Department of Infectious Diseases, Huashan Hospital, Shanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
⁴ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
⁵ Department of Molecular and Cell Biology, University of California, Merced, California; Health Sciences Research Institute, University of California, Merced, California.
⁶ Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China; Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: chu_haiqing@126.com.
⁷ Department of Infectious Diseases, Huashan Hospital, Shanghai Institute of Infectious Disease and Biosecurity and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai, China. Electronic address: huanggh@fudan.edu.cn.

PMID: 37863341
DOI: 10.1016/j.ijantimicag.2023.107010

Abstract

Objectives: Infections caused by azole-resistant Candida tropicalis strains are increasing in clinical settings. The reason for this epidemical change and the mechanisms of C. tropicalis azole resistance are not fully understood.

Methods: In this study, we performed biological and genomic analyses of 239 C. tropicalis strains, including 115 environmental and 124 human commensal isolates.

Results: Most (99.2%) of the isolates had a baseline diploid genome. The strains from both environmental and human niches exhibit similar abilities to survive under stressful conditions and produce secreted aspartic proteases. However, the human commensal isolates exhibited a stronger ability to filament than the environmental strains. We found that 19 environmental isolates (16.5%) and 24 human commensal isolates (19.4%) were resistant to fluconazole. Of the fluconazole-resistant strains, 37 isolates (86.0%) also exhibited cross-resistance to voriconazole. Whole-genome sequencing and phylogenetic analyses revealed that both environmental and commensal isolates were widely distributed in a number of genetic clusters, but the two populations exhibited a close genetic association. The majority of fluconazole-resistant isolates were clustered within a single clade (X).

Conclusions: The combination of hotspot mutations (Y132F and S154F) and genomic expansion of ERG11, which encodes the azole target lanosterol 14-α-demethylase and represents a major target of azole drugs, was a major mechanism for the development of azole resistance. The isolates carrying both hotspot mutations and genomic expansion of ERG11 exhibited cross-resistance to fluconazole and voriconazole. Moreover, the azole-resistant isolates from both the environmental and human commensal niches showed similar genotypes.

Keywords: Candida tropicalis; Drug resistance; ERG11; Fluconazole; Genomic expansion; Voriconazole.

MeSH terms

Antifungal Agents / pharmacology
Antifungal Agents / therapeutic use
Azoles* / pharmacology
Candida tropicalis* / genetics
Drug Resistance, Fungal* / genetics
Fluconazole* / pharmacology
Fungal Proteins / genetics
Genomics
Humans
Microbial Sensitivity Tests
Mutation
Phylogeny
Voriconazole / pharmacology

Substances

Antifungal Agents
Azoles
Fluconazole
Fungal Proteins
Voriconazole