Bacterial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to bactericides, have been studied extensively because of their clinical importance. In comparison, much less is known about the determinants underlying fungicide-tolerant fungal persister formation in vivo. Here, we report that during mouse lung infection, Cryptococcus neoformans forms persisters that are highly tolerant to amphotericin B (AmB), the standard of care for treating cryptococcosis. By exploring stationary-phase indicator molecules and developing single-cell tracking strategies, we show that in the lung, AmB persisters are enriched in cryptococcal cells that abundantly produce stationary-phase molecules. The antioxidant ergothioneine plays a specific and key role in AmB persistence, which is conserved in phylogenetically distant fungi. Furthermore, the antidepressant sertraline (SRT) shows potent activity specifically against cryptococcal AmB persisters. Our results provide evidence for and the determinant of AmB-tolerant persister formation in pulmonary cryptococcosis, which has potential clinical significance.

细菌持续存在是遗传易感细胞的一个亚群，通常处于休眠状态并且对杀菌剂具有耐受性，由于其临床重要性而已被广泛研究。相比之下，人们对体内耐杀菌剂真菌持久存在形成的决定因素知之甚少。在这里，我们报告在小鼠肺部感染期间，新型隐球菌形成对两性霉素 B (AmB) 高度耐受的持续存在，两性霉素 B (AmB) 是治疗隐球菌病的护理标准。通过探索稳定相指示分子和开发单细胞追踪策略，我们发现在肺部，AmB 持续存在在大量产生稳定相分子的隐球菌细胞中富集。抗氧化剂麦角硫因在 AmB 持久性中发挥着特殊且关键的作用，AmB 在系统发育较远的真菌中是保守的。此外，抗抑郁药舍曲林 (SRT) 显示出针对隐球菌 AmB 持续存在的有效活性。我们的结果为肺隐球菌病中AmB耐受性持续存在的形成提供了证据和决定因素，具有潜在的临床意义。