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

In bacteria, antibiotic tolerance, the ability of a susceptible population to survive high doses of cidal drugs, has been shown to compromise therapeutic outcomes. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains unproven. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that glucose, on which the brain depends for fuel, induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. To explore the mechanisms underlying glucose-dependent AmB tolerance mediated by Mig1, we used time-series RNA-seq to evaluate dynamic gene expression in wildtype and mig1Δ fungi after exposure to AmB under both drug-tolerant (glucose) or drug-sensitive (galactose) conditions. 24 samples contain wild type, mig1△, three replicates