Brain glucose induces fungicidal tolerance during fungal meningitis. This study reveals that glucose, a major energy source in the brain, induces tolerance to amphotericin B (AmB) in Cryptococcus neoformans, the leading cause of fungal meningitis. The glucose repression activator Mig1 mediates this tolerance by inhibiting ergosterol synthesis, the target of AmB, and promoting the production of inositolphosphorylceramide (IPC), which competes with AmB for ergosterol. This tolerance limits the efficacy of AmB treatment in mice. When combined with an inhibitor of IPC synthase, aureobasidin A (AbA), AmB shows improved efficacy against cryptococcal meningitis. The findings demonstrate that host-derived metabolites can induce fungicidal tolerance, which significantly weakens therapeutic outcomes. The study highlights the importance of understanding host-pathogen interactions in fungal infections and suggests that targeting IPC synthesis could enhance AmB therapy. The results provide new insights into the mechanisms of fungal tolerance and potential therapeutic strategies for fungal meningitis.Brain glucose induces fungicidal tolerance during fungal meningitis. This study reveals that glucose, a major energy source in the brain, induces tolerance to amphotericin B (AmB) in Cryptococcus neoformans, the leading cause of fungal meningitis. The glucose repression activator Mig1 mediates this tolerance by inhibiting ergosterol synthesis, the target of AmB, and promoting the production of inositolphosphorylceramide (IPC), which competes with AmB for ergosterol. This tolerance limits the efficacy of AmB treatment in mice. When combined with an inhibitor of IPC synthase, aureobasidin A (AbA), AmB shows improved efficacy against cryptococcal meningitis. The findings demonstrate that host-derived metabolites can induce fungicidal tolerance, which significantly weakens therapeutic outcomes. The study highlights the importance of understanding host-pathogen interactions in fungal infections and suggests that targeting IPC synthesis could enhance AmB therapy. The results provide new insights into the mechanisms of fungal tolerance and potential therapeutic strategies for fungal meningitis.