Antifungal activity of the repurposed drug disulfiram against Cryptococcus neoformans .

Autor:	Peng M; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Zhang C; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Duan YY; Affiliated Hospital for Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China., Liu HB; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Peng XY; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Wei Q; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.; Affiliated Hospital for Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China., Chen QY; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Sang H; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China., Kong QT; Department of Dermatology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Jan 11; Vol. 14, pp. 1268649. Date of Electronic Publication: 2024 Jan 11 (Print Publication: 2023).
DOI:	10.3389/fphar.2023.1268649
Abstrakt:	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 . 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 Peng, Zhang, Duan, Liu, Peng, Wei, Chen, Sang and Kong.)
Databáze:	MEDLINE
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