Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus Candida glabrata


Arastehfar A., Daneshnia F., Floyd D. J., Jeffries N. E., Salehi M., Perlin D. S., ...More

mBio, vol.15, no.4, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 15 Issue: 4
  • Publication Date: 2024
  • Doi Number: 10.1128/mbio.00072-24
  • Journal Name: mBio
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Aqualine, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Food Science & Technology Abstracts, MEDLINE, Pollution Abstracts, Directory of Open Access Journals
  • Keywords: Candida glabrata, echinocandin, ex vivo, in vivo, persistence, tolerance
  • Çukurova University Affiliated: Yes

Abstract

Recent epidemiological studies documented an alarming increase in the prevalence of echinocandin-resistant (ECR) Candida glabrata blood isolates. ECR isolates are known to arise from a minor subpopulation of a clonal population, termed echinocandin persisters. Although it is believed that isolates with a higher echinocandin persistence (ECP) are more likely to develop ECR, the implication of ECP needs to be better understood. Moreover, replacing laborious and time-consuming traditional approaches to determine ECP levels with rapid, convenient, and reliable tools is imperative to advance our understanding of this emerging concept in clinical practice. Herein, using extensive ex vivo and in vivo systemic infection models, we showed that high ECP isolates are less effectivelycleared by micafungin treatment and exclusively give rise to ECR colonies. Additionally, we developed a flowcytometry-based tool that takes advantage of a SYTOX-based assay for the stratificationof ECP levels. Once challenged with various collections of echinocandin-susceptible blood isolates, our assay reliably differentiatedECP levels in vitro and predicted ECP levels in real time under ex vivo and in vivo conditions when compared to traditional methods relying on colony-forming unit counting. Given the high and low ECP predictive values of 92.3% and 82.3%, respectively, our assay showed a high agreement with traditional approach. Collectively, our study supports the concept of ECP level determination in clinical settings and provides a robust tool scalable for high-throughput settings. Application of this tool facilitates the interrogation of mutant and drug libraries to further our understanding of persister biology and designing anti-persister therapeutics.