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

• Published in: Nature communications Vol. 14; no. 1; pp. 8369 - 18
• Main Authors: Fan, Xin, Dai, Rong-Chen, Zhang, Shu, Geng, Yuan-Yuan, Kang, Mei, Guo, Da-Wen, Mei, Ya-Ning, Pan, Yu-Hong, Sun, Zi-Yong, Xu, Ying-Chun, Gong, Jie, Xiao, Meng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.12.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 45/47; 45/77; 45/88; 49; 631/181/457/649; 631/326/193/2541; 692/699/255/1672; Antifungal agents; Antifungal Agents - pharmacology; Azoles - pharmacology; Candida tropicalis; Candida tropicalis - genetics; Candidiasis; Clusters; Drug resistance; Drug Resistance, Fungal - genetics; Fungicides; Gene Duplication; Gene sequencing; Genomes; Humanities and Social Sciences; Microbial Sensitivity Tests; multidisciplinary; Multilocus Sequence Typing; Nucleotide sequence; Population genetics; Population studies; Science; Science (multidisciplinary); Whole genome sequencing; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43380-2

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. Candida tropicalis is a cause of invasive candidiasis infection in humans that has been increasingly associated with azole drug resistance. In this study, the authors investigate the genetic basis for azole resistance through analysis of whole-genome sequencing and multilocus sequence typing data.