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Biolistic Transformation of a Fluorescent Tagged Gene into the Opportunistic Fungal Pathogen Cryptococcus neoformans
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Discovery of 5-Nitro-6-thiocyanatopyrimidines as Inhibitors of Cryptococcus neoformans and Cryptococcus gattii

Maureen J Donlin1,2, Thomas R Lane3, Olga Riabova4

  • 1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States.

ACS Medicinal Chemistry Letters
|May 31, 2021
PubMed

Insights

New antifungal drug candidates show promise against Cryptococcus, a dangerous fungal pathogen. These 5-nitro-6-thiocyanatopyrimidine compounds are effective against drug-resistant strains and may offer a new treatment option for cryptococcal meningitis.

Area of Science:

  • Mycology
  • Medicinal Chemistry
  • Computational Biology

Background:

  • Opportunistic fungal infections pose a significant healthcare challenge due to limited drug options and rising antifungal resistance.
  • Cryptococcal meningitis, caused by *Cryptococcus neoformans* and *Cryptococcus gattii*, has high mortality rates despite optimal care.
  • Existing antifungal treatments are limited and face challenges from resistant fungal strains.

Purpose of the Study:

  • To identify novel antifungal drug candidates for treating opportunistic fungal infections.
  • To develop new treatments effective against drug-resistant *Cryptococcus* species.
  • To address the urgent need for improved therapies against cryptococcal meningitis.

Main Methods:

  • Utilized *in vitro* screening and computational machine learning approaches.
  • Synthesized and evaluated a series of 5-nitro-6-thiocyanatopyrimidine derivatives.
  • Tested compound efficacy against *Cryptococcus neoformans* and *Cryptococcus gattii* strains, including fluconazole-resistant isolates.

Main Results:

  • Identified potent 5-nitro-6-thiocyanatopyrimidine antifungal drug candidates.
  • Achieved submicromolar inhibition of *C. neoformans* growth.
  • Demonstrated efficacy against fluconazole-resistant *C. neoformans* and a clinical *C. gattii* strain.
  • Confirmed no antagonistic interactions with existing approved antifungals.

Conclusions:

  • The novel 5-nitro-6-thiocyanatopyrimidine compounds represent promising leads for new antifungal therapies.
  • These candidates offer potential against challenging and resistant *Cryptococcus* infections.
  • Further development could lead to improved treatments for cryptococcal meningitis and other opportunistic mycoses.

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