The common evolution of fungicide persistence in cryptococcosis patients

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SUMMARY Fungicide persistence, the ability of dormant fungal cells to survive lethal drug exposure, undermines treatment efficacy, yet its clinical evolution remains largely unexplored. We assembled a nationwide collection of clinical Cryptococcus neoformans isolates from China and revealed extensive inter-strain variation in amphotericin B (AmB) persistence. This variation can arise from common evolutionary events in patients, generating previously undescribed high-persistence cryptococcal variants refractory to AmB clearance. Genome-wide fitness landscape analysis shows that persistence-associated mutations generally impose minimal fitness costs, facilitating persistence evolution even in fungistatic-resistant and hypervirulent genetic backgrounds. Machine learning identified deficient ACO2 expression as a key predictor of high-persistence clinical isolates. ACO2 deficiency reproduces the high-persistence phenotype by promoting POPC accumulation, which competes with AmB for its target. Moreover, the clinical-stage antifungal T-2307 effectively eliminates high-persistence strains across diverse genetic backgrounds. Collectively, our findings unveil common evolution of fungicide persistence in cryptococcosis patients, representing a previously overlooked clinical concern.

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