دورية أكاديمية
Aneuploidy underlies brefeldin A-induced antifungal drug resistance in Cryptococcus neoformans .
العنوان: | Aneuploidy underlies brefeldin A-induced antifungal drug resistance in Cryptococcus neoformans . |
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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.) |
References: | PLoS Pathog. 2012;8(6):e1002765. (PMID: 22737071) Cell Microbiol. 2017 Jun;19(6):. (PMID: 28061020) Mol Microbiol. 2008 May;68(3):624-41. (PMID: 18363649) Nature. 2010 Nov 11;468(7321):321-5. (PMID: 20962780) Antimicrob Agents Chemother. 2004 Nov;48(11):4377-86. (PMID: 15504867) Nat Commun. 2018 Jul 19;9(1):2834. (PMID: 30026603) Microbiol Spectr. 2021 Oct 31;9(2):e0050821. (PMID: 34612700) Ann Med. 2013 Mar;45(2):194-202. (PMID: 22928964) Mol Biol Evol. 2019 Aug 1;36(8):1768-1782. (PMID: 31028698) Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):9913-8. (PMID: 10954741) Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2877-82. (PMID: 18287014) Antimicrob Agents Chemother. 2005 Jul;49(7):2851-6. (PMID: 15980360) Nat Commun. 2020 Jan 8;11(1):127. (PMID: 31913284) Genetics. 2018 Apr;208(4):1357-1372. (PMID: 29444806) Cold Spring Harb Perspect Med. 2014 Jul 31;4(10):. (PMID: 25081629) Curr Opin Microbiol. 2019 Dec;52:158-164. (PMID: 31765991) mBio. 2022 Aug 30;13(4):e0084222. (PMID: 35862787) Genome Med. 2014 Nov 20;6(11):100. (PMID: 25505934) J Exp Clin Cancer Res. 2018 Nov 9;37(1):272. (PMID: 30413206) Antimicrob Agents Chemother. 2013 Oct;57(10):5026-36. (PMID: 23896475) Clin Microbiol Rev. 1999 Oct;12(4):501-17. (PMID: 10515900) Science. 2006 Jul 21;313(5785):367-70. (PMID: 16857942) Genome Biol. 2014;15(12):550. (PMID: 25516281) Nat Rev Genet. 2020 Jan;21(1):44-62. (PMID: 31548659) PLoS Genet. 2021 Oct 8;17(10):e1009817. (PMID: 34624015) Infect Dis Poverty. 2023 Mar 17;12(1):20. (PMID: 36932414) Genetics. 2021 Jun 24;218(2):. (PMID: 33837402) Microbiol Spectr. 2023 Feb 28;:e0301622. (PMID: 36853047) Nat Rev Microbiol. 2022 Sep;20(9):557-571. (PMID: 35352028) Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9586-9591. (PMID: 30185560) Microbiol Spectr. 2021 Oct 31;9(2):e0072321. (PMID: 34585947) Biochem Soc Trans. 2005 Nov;33(Pt 5):1219-23. (PMID: 16246085) Nat Commun. 2021 Jun 8;12(1):3418. (PMID: 34103502) mBio. 2021 Aug 31;12(4):e0227221. (PMID: 34465026) J Clin Invest. 2019 Mar 1;129(3):999-1014. (PMID: 30688656) Lancet. 2003 Oct 4;362(9390):1142-51. (PMID: 14550704) Antimicrob Agents Chemother. 2020 Dec 16;65(1):. (PMID: 33077664) Fungal Genet Biol. 2017 Nov;108:13-25. (PMID: 28870457) PLoS Biol. 2013 Oct;11(10):e1001692. (PMID: 24204207) Ageing Res Rev. 2009 Jul;8(3):150-9. (PMID: 19491040) Antimicrob Agents Chemother. 1997 Nov;41(11):2471-9. (PMID: 9371352) Front Microbiol. 2023 Apr 11;14:1137083. (PMID: 37113223) Antimicrob Agents Chemother. 1997 Jan;41(1):196-9. (PMID: 8980781) Mutat Res. 2005 Jan 6;569(1-2):29-63. (PMID: 15603751) Antimicrob Agents Chemother. 2017 Apr 24;61(5):. (PMID: 28223384) Methods. 2001 Dec;25(4):402-8. (PMID: 11846609) Mol Cell. 1999 Mar;3(3):275-85. (PMID: 10198630) Lancet Infect Dis. 2017 Aug;17(8):873-881. (PMID: 28483415) J Fungi (Basel). 2020 Nov 27;6(4):. (PMID: 33261213) FEBS Lett. 1997 Jan 2;400(1):80-2. (PMID: 9000517) J Antimicrob Chemother. 2003 Mar;51(3):513-21. (PMID: 12615851) Antimicrob Agents Chemother. 2019 Jan 29;63(2):. (PMID: 30455247) J Bacteriol. 1999 Jan;181(2):444-53. (PMID: 9882657) BMC Genomics. 2011 Oct 27;12:526. (PMID: 22032296) PLoS Pathog. 2010 Apr 01;6(4):e1000848. (PMID: 20368972) Arch Pharm (Weinheim). 2009 Mar;342(3):150-64. (PMID: 19253321) J Clin Microbiol. 1996 Jun;34(6):1531-4. (PMID: 8735111) J Clin Microbiol. 2009 Jan;47(1):117-23. (PMID: 19005141) |
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 |
تدمد: | 2235-2988 |
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DOI: | 10.3389/fcimb.2024.1397724 |