Journal article
Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen Cryptococcus neoformans
ACS infectious diseases, Vol.6(3), pp.529-539
03/13/2020
DOI: 10.1021/acsinfecdis.9b00478
PMCID: PMC7664160
PMID: 32070095
Abstract
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.
Details
- Title: Subtitle
- Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen Cryptococcus neoformans
- Creators
- Sarah R. Beattie - University of IowaNicholas J. Schnicker - University of IowaThomas Murante - University of RochesterKavitha Kettimuthu - The University of Texas Southwestern Medical CenterNoelle S. Williams - The University of Texas Southwestern Medical CenterLokesh Gakhar - University of IowaDamian J. Krysan - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- ACS infectious diseases, Vol.6(3), pp.529-539
- DOI
- 10.1021/acsinfecdis.9b00478
- PMID
- 32070095
- PMCID
- PMC7664160
- NLM abbreviation
- ACS Infect Dis
- ISSN
- 2373-8227
- eISSN
- 2373-8227
- Grant note
- DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: 1R21AI125094
- Language
- English
- Date published
- 03/13/2020
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Medicine Administration; Infectious Disease (Pediatrics)
- Record Identifier
- 9984297424802771
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