High-Throughput Screen in Cryptococcus neoformans Identifies a Novel Molecular Scaffold That Inhibits Cell Wall Integrity Pathway Signaling.

ACS Infect Dis
Authors
Abstract

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.

Year of Publication
2016
Journal
ACS Infect Dis
Volume
2
Issue
1
Pages
93-102
Date Published
2016 Jan 08
DOI
10.1021/acsinfecdis.5b00111
PubMed ID
26807437
PubMed Central ID
PMC4709821
Links
Grant list
R01 AI091422 / AI / NIAID NIH HHS / United States
R01 AI097142 / AI / NIAID NIH HHS / United States