Antifungal drug resistance represents a serious global health threat, necessitating new treatment strategies. Here we investigated collateral sensitivity (CS), in which resistance to one drug increases sensitivity to another, and cross-resistance (XR), in which one drug resistance mechanism reduces susceptibility to multiple drugs, since CS and XR dynamics can guide treatment design to impede resistance development, but have not been systematically explored in pathogenic fungi. We used experimental evolution and mathematical modelling of Candida auris population dynamics during cyclic and combined drug exposures and found that especially CS-based drug cycling can effectively prevent the emergence of drug resistance. In addition, we found that a CS-based treatment switch can actively select against or eradicate resistant sub-populations, highlighting the potential to consider CS in therapeutic decision-making upon resistance detection. Furthermore, we show that some CS trends are robust among different strains and resistance mechanisms. Overall, these findings provide a promising direction for improved antifungal treatment approaches.

抗真菌药物耐药性是一个严重的全球健康威胁，需要新的治疗策略。在这里，我们研究了附带敏感性 （CS），其中对一种药物的耐药性增加了对另一种药物的敏感性，以及交叉耐药性 （XR），其中一种耐药机制降低了对多种药物的敏感性，因为 CS 和 XR 动力学可以指导治疗设计以阻碍耐药性的发展，但尚未在病原真菌中系统探索。我们使用了周期性和联合药物暴露期间耳念珠菌种群动态的实验进化和数学建模，发现特别是基于 CS 的药物循环可以有效防止耐药性的出现。此外，我们发现基于 CS 的治疗转换可以主动选择或根除耐药亚群，突出了在检测到耐药性时在治疗决策中考虑 CS 的潜力。此外，我们表明一些 CS 趋势在不同的菌株和耐药机制中是稳健的。总体而言，这些发现为改进抗真菌治疗方法提供了一个有希望的方向。