High-Throughput Screen in Cryptococcus neoformans Identifies a Novel Molecular Scaffold That Inhibits Cell Wall Integrity Pathway Signaling
Open accessAbstract
Cryptococcus neoformans is one of the most important human fungal pathogens; however, no new therapies have been developed in over 50 years. Fungicidal activity is crucially important for an effective anticryptococal agent and, therefore, we screened 361,675 molecules against C. neoformans using an adenylate kinase release assay that specifically detects fungicidal activity. A set of secondary assays narrowed the set of hits to molecules that interfere with fungal cell wall integrity and identified three benzothioureas with low in vitro mammalian toxicity and good in vitro anticryptococcal (minimum inhibitory concentration = 4 μg/mL). This scaffold inhibits signaling through the cell wall integrity MAP kinase cascade. Structure–activity studies indicate that the thiocarbonyl moiety is crucial for activity. Genetic and biochemical data suggest that benzothioureas inhibit signaling upstream of the kinase cascade. Thus, the benzothioureas appear to be a promising new scaffold for further exploration in the search for new anticryptococcal agents.
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N-substituted benzothioureas (BTUs) are a scaffold capable of inhibiting activation of the cell wall integrity pathway in Cryptococcus spp.
“Through this endeavour, N-substituted benzothioureas (BTUs) were highlighted as a scaffold that is capable of inhibiting activation of the cell wall integrity pathway in Cryptococcus spp.91”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [91]
Alternative high-throughput screening platforms that specifically identify fungicidal molecules have been developed.
“In addition to employing non-traditional compound libraries for the discovery of novel antifungals, alternative high-throughput screening platforms that specifically identify fungicidal molecules have been developed91,92.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [91]
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Treatment strategies for cryptococcal infection: challenges, advances and future outlook
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Self-citation
- Authors
- Hartland, K., Pu, J., Palmer, M., Dandapani, S., Moquist, P. N., Munoz, B., DiDone, L., Schreiber, S. L., & Krysan, D. J.
- Affiliations
- Broad Institute (US)
- Broad Institute of Harvard and MIT , , 7 Cambridge Center , , ,
- University of Rochester Medicine (US)
- Corresponding author
- Krysan, Damian J.
- Venue
- ACS Infectious Diseases
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-11-06
- Volume
- 2
- Issue
- 1
- Pages
- 93-102
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC4709821
- OpenAlex
- W2265238401
- Cited by
- 24
- References
- 32
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 2 · 2017: 1 · 2016: 4
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Infectious Diseases (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (1R01AI091422, 1R01AI097142)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- Cryptococcus neoformans, cell wall integrity signaling, MAP kinase cascade, high-throughput screening, fungicidal activity, structure-activity relationship, molecular scaffolds, antifungal drug discovery
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