Sugar in Brain May Increase Antifungal Drug Tolerance
Cryptococcus neoformans, a fungus that infects the human brain, is the leading cause of fungal meningitis and leads to around 180,000 deaths per year. Currently, the only fungicidal drug available to treat it is amphotericin B, the journal of Nature Microbiology reported.
Despite amphotericin B's excellence in vitro bactericidal activity against C. neoformans, there is high incidence of treatment failure and recurrent infections in cryptococcal meningitis with the cause still unknown.
To address this challenge, researchers at the Institute of Microbiology under the Chinese Academy of Sciences conducted a high-throughput screen, and validated brain tissues from mice and human cerebrospinal fluid, to explore the effect of hundreds of metabolites on the interactions between C. neoformans and amphotericin B.
They identified that glucose in the brain elicits antifungal tolerance through the C. neoformans protein, Mig1, which is a regulator of glucose repression.
The researchers found that in mice, Mig1 inhibits the synthesis of ergosterol, a component of fungal cell membranes, which is the target of amphotericin B, and promotes the production of inositolphosphorylceramide, another component of fungal cell membranes, which competes with amphotericin B for ergosterol, limiting the drug's effectiveness.
The researchers then discovered that using an inhibitor of inositolphosphorylceramide together with amphotericin B improves treatment efficacy against cryptococcal meningitis in mice.
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