دورية أكاديمية
Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus Candida glabrata .
| العنوان: | Echinocandin persistence directly impacts the evolution of resistance and survival of the pathogenic fungus Candida glabrata . |
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| المؤلفون: | Arastehfar A; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Daneshnia F; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.; Institute of Biodiversity and Ecosystem Dynamics (IBED), University of Amsterdam, Amsterdam, The Netherlands., Floyd DJ; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA., Jeffries NE; Center for Regenerative Medicine, Boston, Massachusetts, USA., Salehi M; Department Industrial Engineering Faculty of K.N., Toosi University of Technology, Tehran, Iran., Perlin DS; Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA.; Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.; Georgetown University Lombardi Comprehensive Cancer Center, Washington, District of Columbia, USA., Ilkit M; Division of Mycology, Faculty of Medicine, University of Çukurova, Adana, Türkiye., Lass-Flöerl C; Medical University Innsbruck, Institute of Hygiene and Medical Microbiology, Innsbruck, Austria., Mansour MK; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. |
| المصدر: | MBio [mBio] 2024 Apr 10; Vol. 15 (4), pp. e0007224. Date of Electronic Publication: 2024 Mar 19. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Echinocandins*/pharmacology , Candida glabrata*/genetics, Micafungin/pharmacology ; Drug Resistance, Fungal/genetics ; Microbial Sensitivity Tests ; Antifungal Agents/pharmacology ; Antifungal Agents/therapeutic use ; Anti-Bacterial Agents/pharmacology |
| مستخلص: | 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 effectively cleared by micafungin treatment and exclusively give rise to ECR colonies. Additionally, we developed a flow cytometry-based tool that takes advantage of a SYTOX-based assay for the stratification of ECP levels. Once challenged with various collections of echinocandin-susceptible blood isolates, our assay reliably differentiated ECP 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. Importance: Candida glabrata is a prevalent fungal pathogen able to replicate inside macrophages and rapidly develop resistance against frontline antifungal echinocandins. Multiple studies have shown that echinocandin resistance is fueled by the survival of a small subpopulation of susceptible cells surviving lethal concentrations of echinocandins. Importantly, bacterial pathogens that exhibit high antibiotic persistence also impose a high burden and generate more antibiotic-resistant colonies. Nonetheless, the implications of echinocandin persistence (ECP) among the clinical isolates of C. glabrata have not been defined. Additionally, ECP level determination relies on a laborious and time-consuming method, which is prone to high variation. By exploiting in vivo systemic infection and ex vivo models, we showed that C. glabrata isolates with a higher ECP are associated with a higher burden and more likely develop echinocandin resistance upon micafungin treatment. Additionally, we developed an assay that reliably determines ECP levels in real time. Therefore, our study identified C. glabrata isolates displaying high ECP levels as important entities and provided a reliable and convenient tool for measuring echinocandin persistence, which is extendable to other fungal and bacterial pathogens. Competing Interests: “Michael K. Mansour consults for Clear Creek Bio, Day Zero Diagnostics, Safi, GenMark Diagnostics, NED Biosystems, and Vericel. He received grants from Karius, Danaher, Genentech, and Thermo-Fisher Scientific. He is a medical writer for UpToDate. The remaining authors have nothing to report.” |
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| معلومات مُعتمدة: | R01 AI132638 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: Candida glabrata; echinocandin; ex vivo; in vivo; persistence; tolerance |
| المشرفين على المادة: | 0 (Echinocandins) R10H71BSWG (Micafungin) 0 (Antifungal Agents) 0 (Anti-Bacterial Agents) |
| تواريخ الأحداث: | Date Created: 20240319 Date Completed: 20240411 Latest Revision: 20240425 |
| رمز التحديث: | 20240425 |
| مُعرف محوري في PubMed: | PMC11005346 |
| DOI: | 10.1128/mbio.00072-24 |
| PMID: | 38501869 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mbio.00072-24 |