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Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis

Lei Chen1, Xiuyun Tian1, Lanyue Zhang1,2

  • 1State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

Nature Microbiology
|January 15, 2024
PubMed

Insights

Brain glucose induces fungal tolerance to antifungal drugs like amphotericin B in Cryptococcus neoformans. This discovery offers new strategies for treating fungal meningitis by targeting specific fungal pathways.

Area of Science:

  • Mycology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Antibiotic tolerance compromises treatment outcomes in bacterial infections.
  • Fungicide tolerance induction by host factors in fungal diseases is poorly understood.
  • Cryptococcus neoformans is a significant cause of fungal meningitis.

Purpose of the Study:

  • To investigate host-derived factors that induce fungal tolerance to antifungal drugs.
  • To elucidate the mechanisms of fungal tolerance in Cryptococcus neoformans.
  • To identify novel therapeutic strategies for cryptococcal meningitis.

Main Methods:

  • Systematic evaluation of metabolite-drug-fungal interactions.
  • In vivo studies using mouse models of cryptococcal meningitis.
  • Analysis of ergosterol and inositolphosphorylceramide synthesis pathways.

Main Results:

  • Brain glucose induces tolerance to amphotericin B (AmB) in Cryptococcus neoformans via the Mig1 activator.
  • Mig1-mediated tolerance inhibits ergosterol synthesis and promotes inositolphosphorylceramide production.
  • Combination therapy with AmB and an inositolphosphorylceramide synthase inhibitor (aureobasidin A) improved efficacy in mice.

Conclusions:

  • Host glucose is a critical factor in inducing antifungal tolerance.
  • Targeting Mig1-mediated pathways and inositolphosphorylceramide synthesis offers a promising therapeutic approach.
  • Combined AmB and aureobasidin A demonstrate superior efficacy against cryptococcal meningitis.

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