دورية أكاديمية
أعرض في EDS

Aneuploidy underlies brefeldin A-induced antifungal drug resistance in Cryptococcus neoformans .

التفاصيل البيبلوغرافية
العنوان: Aneuploidy underlies brefeldin A-induced antifungal drug resistance in Cryptococcus neoformans .
المؤلفون: Zhang ZH; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Sun LL; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Fu BQ; Laboratory Department, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China., Deng J; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Jia CL; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Miao MX; Department of Physiology and Pharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China., Yang F; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.; Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China., Cao YB; Institute of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China., Yan TH; Department of Physiology and Pharmacology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
المصدر: Frontiers in cellular and infection microbiology [Front Cell Infect Microbiol] 2024 Jun 20; Vol. 14, pp. 1397724. Date of Electronic Publication: 2024 Jun 20 (Print Publication: 2024).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Media SA Country of Publication: Switzerland NLM ID: 101585359 Publication Model: eCollection Cited Medium: Internet ISSN: 2235-2988 (Electronic) Linking ISSN: 22352988 NLM ISO Abbreviation: Front Cell Infect Microbiol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Lausanne : Frontiers Media SA
مواضيع طبية MeSH: Cryptococcus neoformans*/drug effects , Cryptococcus neoformans*/genetics , Brefeldin A*/pharmacology , Antifungal Agents*/pharmacology , Aneuploidy* , Drug Resistance, Fungal*/genetics, Fluconazole/pharmacology ; Amphotericin B/pharmacology ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Microbial Sensitivity Tests ; Flucytosine/pharmacology ; Humans ; Endoplasmic Reticulum Stress/drug effects
مستخلص: Cryptococcus neoformans is at the top of the list of "most wanted" human pathogens. Only three classes of antifungal drugs are available for the treatment of cryptococcosis. Studies on antifungal resistance mechanisms are limited to the investigation of how a particular antifungal drug induces resistance to a particular drug, and the impact of stresses other than antifungals on the development of antifungal resistance and even cross-resistance is largely unexplored. The endoplasmic reticulum (ER) is a ubiquitous subcellular organelle of eukaryotic cells. Brefeldin A (BFA) is a widely used chemical inducer of ER stress. Here, we found that both weak and strong selection by BFA caused aneuploidy formation in C. neoformans , mainly disomy of chromosome 1, chromosome 3, and chromosome 7. Disomy of chromosome 1 conferred cross-resistance to two classes of antifungal drugs: fluconazole and 5-flucytosine, as well as hypersensitivity to amphotericin B. However, drug resistance was unstable, due to the intrinsic instability of aneuploidy. We found overexpression of AFR1 on Chr1 and GEA2 on Chr3 phenocopied BFA resistance conferred by chromosome disomy. Overexpression of AFR1 also caused resistance to fluconazole and hypersensitivity to amphotericin B. Furthermore, a strain with a deletion of AFR1 failed to form chromosome 1 disomy upon BFA treatment. Transcriptome analysis indicated that chromosome 1 disomy simultaneously upregulated AFR1 , ERG11 , and other efflux and ERG genes. Thus, we posit that BFA has the potential to drive the rapid development of drug resistance and even cross-resistance in C. neoformans , with genome plasticity as the accomplice.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Zhang, Sun, Fu, Deng, Jia, Miao, Yang, Cao and Yan.)
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فهرسة مساهمة: Keywords: AFR1; Cryptococcus neoformans; aneuploidy; antifungal drugs; brefeldin A; cross-resistance
المشرفين على المادة: 20350-15-6 (Brefeldin A)
0 (Antifungal Agents)
8VZV102JFY (Fluconazole)
7XU7A7DROE (Amphotericin B)
0 (Fungal Proteins)
D83282DT06 (Flucytosine)
تواريخ الأحداث: Date Created: 20240705 Date Completed: 20240705 Latest Revision: 20240706
رمز التحديث: 20240706
مُعرف محوري في PubMed: PMC11222406
DOI: 10.3389/fcimb.2024.1397724
PMID: 38966251
قاعدة البيانات: MEDLINE
الوصف
تدمد:2235-2988
DOI:10.3389/fcimb.2024.1397724