Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen Cryptococcus neoformans
Open accessAbstract
Cryptococcus neoformans is one of the most important human fungal pathogens and causes life-threatening meningoencephalitis in immunocompromised patients. The current gold standard therapy for C. neoformans meningoencephalitis is based on medications that are over 50 years old and is not readily available in regions with high disease burden. Here, we report the mycologic, mechanistic, and pharmacologic characterization of a set of benzothioureas with highly selective fungicidal activity against C. neoformans . In addition, to direct antifungal activity, benzothioureas inhibit C. neoformans virulence traits. On the basis of a set of phenotypic, biochemical, and biophysical assays, the benzothioureas (BTUs) inhibit the late secretory pathway (post-Golgi), possibly through a direct interaction with Sav1, an orthologue of the Sec4-class small GTPase. Importantly, pharmacological characterization of the BTUs indicates it readily penetrates the blood–brain barrier. Together, our data support the further development of this scaffold as an antifungal agent with a novel mechanism of action against C. neoformans .
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BTUs are direct inhibitors of the Sec4-class small GTPase Sav1, leading to impaired function of the late post-Golgi secretory pathway.
“Specifically, BTUs were implicated as direct inhibitors of the Sec4-class small GTPase Sav1, leading to impaired function of the late post-Golgi secretory pathway and highlighting a unique way to compromise cell wall integrity and inhibit fungal cell growth95.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [95]
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Treatment strategies for cryptococcal infection: challenges, advances and future outlook
Iyer, K. R., Revie, N. M., Fu, C., Robbins, N., & Cowen, L. E. (2021) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00511-0 · Cited by 363 · see citing works
- Authors
- Beattie, S. R., Schnicker, N. J., Murante, T., Kettimuthu, K., Williams, N. S., Gakhar, L., & Krysan, D. J.
- Affiliations
- University of Iowa (US)
- University of Rochester Medicine (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Krysan, Damian J.
- Venue
- ACS Infectious Diseases
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-02-18
- Volume
- 6
- Issue
- 3
- Pages
- 529-539
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC7664160
- OpenAlex
- W3007256597
- Cited by
- 10
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 1 · 2021: 3
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (1R21AI125094)
- 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
- Cryptococcus neoformans, antifungal agents, SAV1, fungal virulence, meningoencephalitis, blood-brain barrier penetration, antifungal drug development
- MeSH terms
- Animals, Antifungal Agents, Benzene, Blood-Brain Barrier, Brain, Cryptococcus neoformans, Female, Humans, Microbial Sensitivity Tests, Thiourea, Virulence, Mice, Secretory Pathway
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