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Novel Inhibitors Targeting Urease Promote Fungicidal and Antivirulence Effects in Cryptococcus

Thayná Lopes Barreto1, Nathália Evelyn Morais Costa2, Nathalia Monteiro Lins Freire3

  • 1Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, 1374 Prof. Lineu Prestes Avenue, São Paulo, São Paulo 05508-000, Brazil.

ACS Omega
|July 28, 2026
PubMed

Insights

New synthetic urease inhibitors show potent antifungal activity against Cryptococcus species. Compounds AF55 and AF57 are promising candidates, inhibiting urease and multiple virulence factors for cryptococcosis treatment.

Area of Science:

  • Mycology
  • Medicinal Chemistry
  • Biochemistry

Background:

  • Cryptococcosis is a severe fungal infection caused by Cryptococcus species, often leading to fatal meningitis.
  • Urease is a key virulence factor in Cryptococcus, facilitating survival and spread, making it a potential antifungal target absent in humans.

Purpose of the Study:

  • To synthesize and evaluate novel urease inhibitors against Cryptococcus growth and urease activity.
  • To characterize the inhibition mechanisms and assess the impact of inhibitors on Cryptococcus virulence factors.

Main Methods:

  • Synthesis of a library of synthetic urease inhibitors.
  • In vitro evaluation of antifungal activity and urease inhibition.
  • Enzyme kinetics analysis and molecular dynamic simulations.
  • Assessment of capsule thickness, membrane permeability, and melanin production.

Main Results:

  • Four lead compounds (AF19, AF36, AF55, AF57) demonstrated fungicidal activity and urease inhibition at micro- to nanomolar concentrations.
  • Distinct inhibition mechanisms were elucidated: competitive, noncompetitive, and mixed-type inhibition.
  • Inhibitors reduced capsule thickness and increased membrane permeability; AF55 and AF57 also suppressed melanin production.

Conclusions:

  • Urease inhibitors AF55 and AF57 show significant promise as anticryptococcal agents.
  • These candidates exhibit potent urease inhibition, fungicidal effects, and multi-virulence factor targeting.
  • Favorable predicted pharmacokinetic and toxicological profiles support their further development for cryptococcosis treatment.

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