Brain glucose induces fungicidal tolerance during fungal meningitis

Abstract 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. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice and occurs through inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A (AbA), shows a better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies. Our discoveries provide evidence of host metabolite-induced fungicidal tolerance, which limits treatment efficacy for fungal meningitis.