Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans
Open accessAbstract
Fungal infections have become clinically challenging owing to the emergence of drug resistance in invasive fungi and the rapid increase in the number of novel pathogens. The development of drug resistance further restricts the use of antifungal agents. Therefore, there is an urgent need to identify alternative treatments for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a good human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. However, the effect of DSF on Cryptococcus is yet to be thoroughly investigated. This study investigated the antifungal effects and the mechanism of action of DSF against C. neoformans to provide a new theoretical foundation for the treatment of Cryptococcal infections. In vitro studies demonstrated that DSF inhibited Cryptococcus growth at minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects have been observed for DSF with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. DSF exerts significant protective effects and synergistic effects combined with 5-FU for Galleria mellonella infected with C. neoformans. Mechanistic investigations showed that DSF dose-dependently inhibited melanin, urease, acetaldehyde dehydrogenase, capsule and biofilm viability of C. neoformans. Further studies indicated that DSF affected C. neoformans by interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways include acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter), and iron-sulfur cluster transporter. These findings provide novel insights into the application of DSF and contribute to the understanding of its mechanisms of action in C. neoformans.
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DIS disrupts key fungal cell processes and exhibits potent antifungal activity against Candida and Cryptococcus species by inhibiting both growth and biofilm formation.
“DIS disrupts key fungal cell processes (metabolism, replication, and membrane transport), exhibiting potent antifungal activity against Candida and Cryptococcus species by inhibiting both growth and biofilm formation.111,112,113”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [113]
The Abstract and Results §3.10 report that disulfiram inhibits Cryptococcus growth and reduces biofilm viability; the Abstract also links its effects to replication, metabolism, and membrane transport. The Introduction reports activity against Candida albicans, but its Candida biofilm example involves disulfiram derivatives combined with amphotericin B, not disulfiram alone. Thus this source does not establish the claimed inhibition of both growth and biofilm formation by disulfiram across both genera. (LLM, conf=0.86)
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Self-citation
- Authors
- Peng, M., Zhang, C., Duan, Y.-Y., Liu, H.-B., Peng, X.-Y., Wei, Q., Chen, Q.-Y., Sang, H., & Kong, Q.-T.
- Affiliations
- Nanjing General Hospital of Nanjing Military Command (CN)
- Zhongyuan University of Technology (CN)
- Corresponding author
- Sang, Hong
- ORCID
- Sang, Hong
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2024-01-11
- Volume
- 14
- Pages
- 1268649-1268649
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC10808519
- OpenAlex
- W4390744821
- Cited by
- 9
- References
- 70
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- disulfiram, Cryptococcus neoformans, antifungal activity, drug repurposing, combination antifungal therapy, 5-fluorocytosine, melanin, urease, acetaldehyde dehydrogenase, capsule formation, biofilm, Galleria mellonella infection model, mechanism of action, drug resistance, ABC transporters, catalase
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