The common evolution of fungicide persistence in cryptococcosis patients

Fungicide persistence, a trait allowing dormant fungal cells to survive lethal drug exposure, poses challenges to treatment effectiveness. However, its clinical evolution has not been thoroughly investigated. Researchers have compiled a nationwide collection of clinical Cryptococcus neoformans isolates from China, uncovering significant strain-to-strain variation in amphotericin B (AmB) persistence.

This variability arises from common evolutionary processes in patients, leading to the emergence of previously unknown high persistence cryptococcal variants that resist AmB clearance. Genome-wide analysis of fitness landscapes reveals that mutations associated with persistence typically cause minimal fitness costs, enabling persistence evolution even in resistant and highly virulent genetic backgrounds.

Machine learning analysis identified deficient ACO2 expression as a crucial factor predicting high persistence in clinical isolates. ACO2 deficiency can replicate the high persistence phenotype by promoting POPC accumulation, which competes with AmB for its target. Furthermore, the clinical antifungal T-2307 effectively eliminates high persistence strains across various genetic backgrounds.

Overall, these findings shed light on the common evolution of fungicide persistence in cryptococcosis patients, highlighting a previously neglected clinical issue.