Benzothiourea Derivatives Target the Secretory Pathway of the Human Fungal Pathogen Cryptococcus neoformans

Sarah R. Beattie, Nicholas J. Schnicker, Thomas Murante, Kavitha Kettimuthu, Noelle S. Williams, Lokesh Gakhar, Damian J. Krysan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)529-539
Number of pages11
JournalACS infectious diseases
Volume6
Issue number3
DOIs
StatePublished - Mar 13 2020

Keywords

  • Cryptococcus
  • antifungal
  • blood-brain barrier
  • fungicidal
  • secretory pathway

ASJC Scopus subject areas

  • Infectious Diseases

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