The role of glucose in inducing tolerance to amphotericin B for fungal meningitis treatment

The role of glucose in inducing tolerance to amphotericin B for fungal meningitis treatment – A new study published in Nature Microbiology sheds light on how the fungus Cryptococcus neoformans develops tolerance to amphotericin B (AmB), the only fungicidal drug available for treating fungal meningitis.

C. neoformans causes meningitis, a deadly disease claiming 180,000 lives annually.
AmB works by targeting ergosterol, a vital component of fungal cell membranes.
Genetic resistance to AmB is rare in meningitis-causing fungi, but clinical outcomes depend heavily on AmB susceptibility. Fungal tolerance, where subpopulations survive despite drug concentrations exceeding minimal inhibitory concentration (MIC), is poorly understood in vivo.

Details of study

Researchers investigated how host metabolites affect AmB efficacy against C. neoformans. A metabolite-drug screening using a BIOLOG phenotype microarray identified glucose as a potential inducer of AmB tolerance. Time-kill curve assays confirmed a positive correlation between glucose concentration and tolerance.
In human cerebrospinal fluid (CSF), the main site of infection, AmB tolerance was observed, abolished by removing glucose with glucose oxidase. Mig1, a fungal regulator, was identified as the key player in glucose-induced AmB tolerance.

Key findings

  • Brain glucose activates Mig1, leading to glucose repression (GR) and AmB tolerance.
  • Mig1 inhibits ergosterol synthesis while promoting inositolphosphorylceramide (IPC) production, competing with AmB for ergosterol.
  • Animal models show Mig1’s essential role in AmB tolerance but not resistance.
  • Disrupting Mig1 alters membrane lipid composition, suggesting its critical link to tolerance and membrane integrity.
  • Mig1 emerges as a potential therapeutic target to improve clinical outcomes.
  • AbA, another antifungal drug, enhances AmB activity against tolerant C. neoformans.
  • Combining AbA and AmB in a mouse model of meningitis demonstrates superior therapeutic efficacy compared to the standard AmB-flucytosine combination. Study source

Symptoms of fungal meningitis

The symptoms of fungal meningitis can vary depending on the specific type of fungus causing the infection. However, some common symptoms include:

  • Headache
  • Fever
  • Nausea and vomiting
  • Stiff neck
  • Photophobia (eyes being more sensitive to light)
  • Altered mental status (confusion)

These symptoms may not appear suddenly, as with acute bacterial meningitis, but rather gradually over time. Fungal meningitis is most commonly caused by Cryptococcus neoformans, a yeast or fungus commonly found in the environment, including soil. Treatment typically involves antifungal medication, such as amphotericin B, flucytosine, and fluconazole. Now that you are done reading “The role of glucose in inducing tolerance to amphotericin B for fungal meningitis treatment” next

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