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

Kate Hartland; Jun Pu; Michelle Palmer; Sivaraman Dandapani; Philip N Moquist; Benito Munoz; Louis DiDone; Stuart L Schreiber; Damian J Krysan

doi:10.1021/acsinfecdis.5b00111

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

Journal article

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

Kate Hartland, Jun Pu, Michelle Palmer, Sivaraman Dandapani, Philip N Moquist, Benito Munoz, Louis DiDone, Stuart L Schreiber and Damian J Krysan

ACS infectious diseases, Vol.2(1), pp.93-102

01/08/2016

DOI: 10.1021/acsinfecdis.5b00111

PMID: 26807437

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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.

mitogen-activated protein kinase

antifungal

yeast cell wall

cell wall integrity pathway

Cryptococcus neoformans

high-throughput screening

Details

Title: Subtitle: High-Throughput Screen in Cryptococcus neoformans Identifies a Novel Molecular Scaffold That Inhibits Cell Wall Integrity Pathway Signaling
Creators: Kate Hartland - Center for the Science of Therapeutics
Jun Pu - Center for the Science of Therapeutics
Michelle Palmer - Center for the Science of Therapeutics
Sivaraman Dandapani - Center for the Science of Therapeutics
Philip N Moquist - Center for the Science of Therapeutics
Benito Munoz - Center for the Science of Therapeutics
Louis DiDone - Department of Pediatrics and
Stuart L Schreiber - Center for the Science of Therapeutics
Damian J Krysan - Department of Pediatrics and
Resource Type: Journal article
Publication Details: ACS infectious diseases, Vol.2(1), pp.93-102
DOI: 10.1021/acsinfecdis.5b00111
PMID: 26807437
NLM abbreviation: ACS Infect Dis
ISSN: 2373-8227
eISSN: 2373-8227
Publisher: American Chemical Society
Grant note: DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: 1R01AI091422, 1R01AI097142
Language: English
Date published: 01/08/2016
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
Record Identifier: 9984093359602771

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