Candida auris is a growing concern due to its resistance to antifungal drugs, particularly amphotericin B (AMB), detected in 30 to 60% of clinical isolates. However, the mechanisms of AMB resistance remain poorly understood. Here we investigated 441 in vitro- and in vivo-evolved C. auris lineages from 4 AMB-susceptible clinical strains of different clades. Genetic and sterol analyses revealed four major types of sterol alterations as a result of clinically rare variations in sterol biosynthesis genes ERG6, NCP1, ERG11, ERG3, HMG1, ERG10 and ERG12. In addition, aneuploidies in chromosomes 4 and 6 emerged during resistance evolution. Fitness trade-off phenotyping and mathematical modelling identified diverse strain- and mechanism-dependent fitness trade-offs. Variation in CDC25 rescued fitness trade-offs, thereby increasing the infection capacity. This possibly contributed to therapy-induced acquired AMB resistance in the clinic. Our findings highlight sterol-modulating mechanisms and fitness trade-off compensation as risks for AMB treatment failure in clinical settings.

耳念珠菌因其对抗真菌药物耐药性而日益受到关注，尤其是两性霉素 B （AMB），在 30% 至 60% 的临床分离株中检测到。然而，AMB 抵抗的机制仍然知之甚少。在这里，我们研究了来自 4 个不同分支的 AMB 敏感临床菌株的 441 个体外和体内进化的耳念珠菌谱系。遗传和甾醇分析揭示了甾醇生物合成基因 ERG6 、 NCP1 、 ERG11 、 ERG3 、 HMG1 、 ERG10 和 ERG12 临床罕见变异导致的四种主要类型的甾醇改变。此外，4 号和 6 号染色体中的非整倍体在抗性进化过程中出现。适应度权衡表型和数学建模确定了不同的应变和机制依赖性适应度权衡。CDC25 的变化挽救了健身权衡，从而提高了感染能力。这可能导致临床上治疗诱导的获得性 AMB 耐药。我们的研究结果强调了甾醇调节机制和健身权衡补偿是临床环境中 AMB 治疗失败的风险。