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Background <p>Candidemia caused by <i>Candida glabrata</i> is a serious fungal infection, and rising echinocandin resistance presents a significant clinical challenge. Understanding the drug susceptibility profiles, molecular epidemiology, and mechanisms underlying adaptive echinocandin resistance in <i>C. glabrata</i> is crucial.</p> Results <p>A total of 106 <i>C. glabrata</i> strains were isolated from blood cultures of 103 candidemia patients across three medical centers in eastern China. Transcriptome sequencing and whole-genome sequence analysis were used to explore the genomic characteristics of echinocandin-resistant strains. Multi-locus sequence typing (MLST) categorized the isolates into 11 sequence types (STs), with ST7 being the most prevalent (67.9%). Drug susceptibility testing revealed a fluconazole resistance rate of 21.7%, while non-wild-type rates for voriconazole, itraconazole, and posaconazole were 23.6%, 7.5%, and 6.6%, respectively. One isolate (Q2-2) was resistant to all three echinocandins. Two isolates were resistant to micafungin and anidulafungin, respectively. Compared to the echinocandin-sensitive strains, the expression of the <i>Chitin synthetase 3</i> (<i>CHS3</i>) gene was significantly upregulated in echinocandin-resistant strains. Functional analysis of a <i>CHS3</i>-overexpressing strain (ATCC2001-<i>CHS3-</i>OE), generated through homologous recombination, confirmed echinocandin resistance. Conversely, a <i>CHS3</i> knockout strain (Q2-2-<i>CHS3</i>Δ) exhibited susceptibility to echinocandins.</p> Conclusions <p>Our findings suggest that <i>CHS3</i> plays a critical compensatory role in echinocandin resistance in <i>C. glabrata</i>, offering a promising target for developing future antifungal strategies.</p>

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Molecular characterization of Echinocandin resistance and the CHS3-mediated adaptive response in Candida glabrata bloodstream infections in Eastern China

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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  • Peishan Cong,
  • Biao Wang,
  • Hong He,
  • Xiaoying Li,
  • Lijing Peng,
  • Ji Liu,
  • Hui Guo,
  • Guirong Sun

摘要

Background

Candidemia caused by Candida glabrata is a serious fungal infection, and rising echinocandin resistance presents a significant clinical challenge. Understanding the drug susceptibility profiles, molecular epidemiology, and mechanisms underlying adaptive echinocandin resistance in C. glabrata is crucial.

Results

A total of 106 C. glabrata strains were isolated from blood cultures of 103 candidemia patients across three medical centers in eastern China. Transcriptome sequencing and whole-genome sequence analysis were used to explore the genomic characteristics of echinocandin-resistant strains. Multi-locus sequence typing (MLST) categorized the isolates into 11 sequence types (STs), with ST7 being the most prevalent (67.9%). Drug susceptibility testing revealed a fluconazole resistance rate of 21.7%, while non-wild-type rates for voriconazole, itraconazole, and posaconazole were 23.6%, 7.5%, and 6.6%, respectively. One isolate (Q2-2) was resistant to all three echinocandins. Two isolates were resistant to micafungin and anidulafungin, respectively. Compared to the echinocandin-sensitive strains, the expression of the Chitin synthetase 3 (CHS3) gene was significantly upregulated in echinocandin-resistant strains. Functional analysis of a CHS3-overexpressing strain (ATCC2001-CHS3-OE), generated through homologous recombination, confirmed echinocandin resistance. Conversely, a CHS3 knockout strain (Q2-2-CHS3Δ) exhibited susceptibility to echinocandins.

Conclusions

Our findings suggest that CHS3 plays a critical compensatory role in echinocandin resistance in C. glabrata, offering a promising target for developing future antifungal strategies.