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| Status |
Public on Dec 31, 2023 |
| Title |
Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans. |
| Organism |
Cryptococcus neoformans |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Fungal infections have become a clinical challenge due to the emergence of drug-resistance of invasive fungi and a rapid increase of novel pathogens. The development of drug resistance has further restricted the use of antifungal agents. Therefore, there is anurgentneedto searchforalternativetreatmentoptions for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a high human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. In contrast, the effect of DSF on Cryptococcus has yet to be thoroughly researched. This study investigated the antifungal effect and mechanism of DSF againstC. neoformansto provide a new theoretical foundation for treating Cryptococcal infections. In vitro studies demonstrated that DSF inhibitedCryptococcusat minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects were also observed with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. In vivo, DSF exerted asignificantprotectiveeffectforGalleria mellonella infected with C. neoformans.Mechanistic investigations showed that DSF dose-dependently inhibited the melanin, urease, acetaldehyde dehydrogenase, capsule, and biofilm formation or viability ofC. neoformans.Further study indicated DSF affectedC. neoformansby interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways included acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter) AFR2, and iron-sulfur cluster transporter ATM1. These findings contribute to the understanding of mechanisms inC. neoformans, and provide new insights for the application of DSF.
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| Overall design |
To investigate further mechanisms of DSF against C. neoformans, we analyzed the regulation of the expression at the transcriptional level. A1-A3 (parallel replicates) were H99 control groups, and B1-B3 were H99 treated with 4 μg/mL of disulfiram through sequencing of the RNA-seq.
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| Contributor(s) |
Peng M, Zhang C, Duan Y, Liu H, Peng X, Wei Q, Chen Q, Sang H, Kong Q |
| Citation(s) |
38273827 |
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| Submission date |
Nov 29, 2023 |
| Last update date |
Feb 09, 2024 |
| Contact name |
Min Peng |
| E-mail(s) |
beidoumaimai@gmail.com
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| Phone |
18205018301
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| Organization name |
Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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| Lab |
Department of Dermatology
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| Street address |
No. 305 Zhongshan East Road, Xuanwu District, Nanjing, Jiangsu Province, China 210002
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| City |
Nanjing |
| State/province |
Jiangsu |
| ZIP/Postal code |
210002 |
| Country |
China |
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| Platforms (1) |
| GPL28713 |
Illumina NovaSeq 6000 (Cryptococcus neoformans) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA1046536 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE248987_B-vs-A-all.gene.txt.gz |
976.8 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
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